Accepted Manuscript Title: Sniping the Scout: Targeting the key molecules in dendritic cell functions for treatment of autoimmune diseases Author: Xing Li Yanping Han Erwei Sun PII: DOI: Reference:
S1043-6618(16)30096-2 http://dx.doi.org/doi:10.1016/j.phrs.2016.02.023 YPHRS 3083
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Pharmacological Research
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Please cite this article as: Li Xing, Han Yanping, Sun Erwei.Sniping the Scout: Targeting the key molecules in dendritic cell functions for treatment of autoimmune diseases.Pharmacological Research http://dx.doi.org/10.1016/j.phrs.2016.02.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Sniping the Scout: Targeting the key molecules in dendritic cell functions for treatment of autoimmune diseases
Authors: Xing Lia,b, Yanping Hanc and Erwei Suna,b,*
a Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. b Institute of Clinical Immunology, Academy of Orthopedics·Guangdong Province, China. c Hospital of South China Normal University, Guangzhou, China.
* Address correspondence to Erwei Sun M.D., Ph.D.: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Avenue West, Tianhe District, Guangzhou 510630, China. E-mail: [email protected], Tel：+86-20-682784421.
Abstract Dendritic cells (DCs) are a power tool for manipulating immune system. They play important roles in the induction of immunity as well as inducing intrathymic and peripheral tolerance. After generated from stem cells in the bone marrow, DCs traffic to the peripheral tissues, where they capture and process antigens, express lymphocyte co-stimulators, migrate to the secondary lymph organs and present the processed antigen to naive T cells to either activate or tolerize them. These processes are modulated subtly and influenced by various factors. Aberrant regulation of the processes may cause autoimmunity. Investigation into the biology of DCs and the molecules and mechanisms that regulate them helps us understanding the pathogenesis of autoimmune diseases and reveals numerous steps for pharmacological manipulation. In this review, we made a sketch line of the critical events of DC biology that are potential pharmacologic targets for the treatment of autoimmune diseases. Keywords: Autoimmune diseases; Dendritic cells; T helper ; Rheumatoid arthritis; Systemic lupus erythematosus; Chemical compounds studied in this article Dexamethasone (PubChem CID: 5743); Vitamin D3 (PubChem CID: 5280795); rapamycin (PubChem CID: 5284616); Aspirin (PubChem CID: 2244); N-acetyl-L-cysteine (PubChem CID: 12035); mycophenolate mofetil (PubChem CID: 5281078); Butyric acid (PubChem CID: 264); rosiglitazone (PubChem CID: 77999); Sanglifehrin A (PubChem CID: 5388925); Cyclosporin A (PubChem CID: 5284373); Tacrolimus (PubChem CID: 445643); FTY720 (PubChem CID: 107969); Chloroquine (PubChem CID: 2719); Troglitazone (PubChem CID: 5591); Leflunomide (PubChem CID: 3899); Triptolide (PubChem CID: 107985); Apigenin (PubChem CID: 5280443); Quercetin (PubChem CID: 5280343); Chrysin (PubChem CID: 5281607); Fumarates (PubChem CID: 5281069); Auranofin (PubChem CID: 24199313); Glatiramer acetate (PubChem CID: 3081884); Trichostatin A (PubChem CID: 444732); Sunitinib (PubChem CID: 5329102); Oenothein B (PubChem CID: 16132398); Tofacitinib (PubChem CID: 9926791); Fostamatinib (PubChem CID: 11671467); Vasoactive intestinal peptide (PubChem CID: 16129679); TGF-β (PubChem CID: 56842206); IL-10 (PubChem CID: 146070).
1. Introduction The immune system provides protection against infection and maintains immune homeostasis. Dendritic cells (DCs) play a central role in the induction of immunity as well as inducing intrathymic and peripheral tolerance. Clinical autoimmunity arises as a result of aberrant regulation of the immune responses [1]. The development of autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus(SLE), requires three different but related processes: disruption of immune tolerance, development of chronic inflammation in one or several organs, and tissue destruction and their harmful effects [2]. Classical treatment for autoimmune diseases is usually a combination of anti-inflammatory, immunosuppressive drugs and biological agents that are designed to block the activity of pro-inflammatory cytokines and lymphocytes as the primary cellular targets. However, the strategy is not so effective in controlling symptoms and disease progression. Accumulating evidence indicates that the central role of DCs in immunity and tolerance is an indispensable component in the pathogenesis of autoimmune diseases [3]. Therefore, targeting DC functions maybe a potential and valuable therapy for the control of autoimmune diseases. DCs
represent
a
heterogeneous
population
of
uniquely
well-equipped
antigen-presenting cells (APCs) with distinct developmental origins, phenotype markers and immunological functions. After generated from stem cells in the bone marrow, DCs are generally immature and traffic to the peripheral tissues, where they undergo several molecular events (namely antigen uptake, phenotypic and functional maturation, migration to the secondary lymphoid organs and present acquired antigens to naive T lymphocytes). Then, they instruct naive T cells to differentiate toward T helper (Th) -1(Th1), Th2, Th17 or regulatory T cell (Treg) cells as well as to promote maturation of antibody-producing B cells [4, 5]. These processes enable DCs to behave as critical sentinels to eliminate invading pathogens, to induce and regulate of most adaptive immune responses and to maintain tolerance and immune homeostasis [6-9]. Disregulation of these processes may cause imbalance of immune responses and lead to autoimmunity. Animal studies indicate that DCs play important
roles in the initiation and perpetuation of autoimmune diseases [10]. In this review, we present a description of key molecules and mechanisms that regulate DC differentiation, endocytosis, maturation and migration, especially focusing on their significances or potentials as pharmacological drugs or agents in anti-inflammation or immunosuppression for autoimmune diseases.
2. Molecular control of DC biology in autoimmunity 2.1 DC differentiation in autoimmunity After several decades of research, we have known that DCs stem from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as an unique hematopoietic branch [10, 11]. Accumulated evidence suggests different DC lineages play different roles in the maintenance of immune homeostasis via induction of immune tolerance and regulation. Under the mediation of some factors, DC precursors can be instructed to differentiate into immunogenic DCs and tolerogenic DCs. Immunogenic DCs have the ability of up-regulation the expression of co-stimulatory molecules (CD40, CD80 and CD86), MHC class II molecules and proinflammatory cytokines such as interleukin-12 (IL-12), tumor necrosis factor (TNF-α) and IL-6, and presenting antigens to specific T cells to elicit adaptive immune responses. Conversely, although tolerogenic DCs retain the ability of presenting antigens to specific T cells, they downregulate the expression of co-stimulatory molecules and proinflammatory cytokines, upregulate the expression of inhibitory molecules and anti-inflammatory cytokines and are resistant to maturation-inducing signals. The process is crucial for maintenance of immune homeostasis and control of autoimmune disorders. Hence, molecular control of DC differentiation maybe the pharmacological potential targets for the control of autoimmune diseases. Previous reviews have reported that pharmacological effects on DC differentiation and expansion can be achieved by immunomodulatory drugs, such as corticosteroids [12, 13], vitamin D3 [14-16], or corticosteroids plus vitamin D3 [13, 17-22], rapamycin [23-27], aspirin [28-30], N-acetyl-L-cysteine [31], mycophenolate mofetil [32, 33], butyric acid [34-36], rosiglitazone [37, 38], rabeximod [39] , n-3
fatty acid [40] and serial chinese herbal medicine [41]. These agents that have been widely used in the treatment of autoimmune diseases are previously reported to block DC differentiation quantitatively by antagonizing the effects of several key molecules, such as hematopoietic cytokines. Generally different hematopoietic molecules control the differentiation and expansion of bone-marrow(BM) cells toward DC specific lineage and maintain DC homeostasis in the periphery [10]. Here, we will present key hematopoietic cytokines that control DC differentiation and their significance in the treatment of autoimmune diseases.
FMS-like tyrosine kinase-3 Ligand (Flt3L) is a key mediators for DC generation [42]. Loss of Flt3 expression in hematopoietic progenitors correlates with the loss of DC differentiation potential [43, 44]. Treatment with Flt3L tyrosine kinase inhibitors or genetic deletion of Flt3L gene in mice leads to 10-fold decrease of pDCs and DCs in lymphoid organs [45], whereas enforcement of Flt3L expression in progenitors that lack the ability to develop into DC restores some DC developmental potential [46]. Prior studies showed that Flt3L was associated with autoimmune pathogenesis. In rheumatoid arthritis, Flt3L is increased in synovial fluid and correlated with active lesions [47]. In collagen-induced arthritis, Flt3L deficiency mice showed a marked increase in the scores and incidence of arthritis in both acute and chronic phases of CIA model mice as compared with wild type mice [48]. A Flt3-Flt3L pathway inhibitor sunitinib can reduce the intensity of synovitis and the incidence of bone destruction in bovine serum albumin (mBSA)-induced arthritis, which was achieved partly by the inhibition on DC differentiation [49]. Whereas increasing the number of DCs by Flt3L injection leads to an increase in the number of regulatory T cells, which contributes to the protection of mice from developing type 1diabetes(T1D) [50]. Due to the dual effects of Flt3L in both promoting and suppressing autoimmunity, the effects of Flt3L on DC precursors at their different developmental stages during the progress of autoimmune diseases need further investigation.
Granulocyte-macrophage colony stimulating factor(GM-CSF), a hematopoietic growth factor that regulates the differentiation of the myeloid lineage genitor cells, plays a critical role in the differentiation of mouse and human hematopoietic progenitors and monocytes into DCs. Accumulated evidence has shown that GM-CSF affects DCs on multiple levels during the pathogenesis of autoimmune diseases [51-54]. Under the influence of elevated GM-CSF, circulating inflammatory monocytes develops into inflammatory DCs that can present self-antigens to T cells and elicit autoimmune responses [55, 56]. Moreover, after antigen uptake and stimulation by the GM-CSF, DCs acquire enhanced life span and presentation ability to active T cells in the lymph nodes and cause autoimmunity [55]. Prior experiments in vitro showed that the GM-CSF stimulated monocyte-derived DC (moDC) maintained
their
inflammatory
property
and
increased
the
secretion
of
pro-inflammatory cytokines TNF-α and IL-6 [56, 57]. And GM-CSF could stimulate immature myeloid cells to differentiate into DCs in the central nervous system (CNS) and exacerbate experimental autoimmune encephalomyelitis (EAE) [58, 59]. Whereas apart from its key roles in the initiation and progression of DC-mediated autoimmunity, GM-CSF also suppresses the immune responses via its effect on DCs. Previous studies have reported that low-dose GM-CSF prevents the development of various autoimmune diseases in mice, through induction of tolerogenic CD8- myeloid DCs from bone marrow precursors and expansion of Foxp3+Tregs [60, 61]. Due to crucial role of GM-CSF in the differentiation and expansion of DCs, currently three anti-GM-CSF antibodies (CAM-3001, MOR103 and KB003) are tested for the pre-clinical treatment of diseases such as multiple sclerosis(MS), RA and asthma. The results showed rapid and significant beneficial effects on autoimmune diseases with no or less unexpected safety concerns [62-64].
Macrophage colony-stimulating factor (M-CSF), also named CSF-1, is a hematopoietic cytokine that mediates the proliferation and differentiation of macrophages [65]. And, M-CSF binds specifically to its receptor(CSF-1R) and partially regulates the differentiation or survival of nonlymphoid DCs [66, 67].
Epidermal langerhans cell (LCs) are totally absent in Csf-1R deficiency mice [68]. In the presence of M-CSF, circulating inflammatory monocytes develop into tolerogenic DCs that maintain the ability of antigen presentation, whereas downregulate expression of co-stimulatory molecules and proinflammatory cytokines [69]. In addition, injection of M-CSF increases both lymphoid organ pDCs and DCs in mice [70, 71]. Taken together, given their crucial roles in DC and autoimmunity, hematopoietic cytokines(e.g Flt3L, GM-CSF, M-CSF) can serve as potential targets to affect DC genesis as well as functions to prevent the development of autoimmune disease.
2.2 DC endocytosis in autoimmunity Haematopoietic stem cells differentiate into immature DCs that are recruited to peripheral tissues, where they continuously take up and process antigens by different endosomal
pathways
[11].
Previous
studies
have
reported
that
several
immunosuppressive mediators potently manipulate the function of DC endocytosis via distinct mechanisms. Some agents, like corticosteroids [12], vitamin D3 [14, 15] ,aspirin [34] and fumarates [72] inhibit phenotypic and functional DC maturation, and
consequently
enhance
endocytic
capacity.
Whereas
some
other
immunosuppressors suppress DC endocytosis by down-regulating the expression of DC endocytosis receptors in a DC-maturation-independent manner. The main agents are rapamycin, sanglifehrin, cyclosporine A (CsA) [34, 73, 74] and quercetin [75]. In the steady state, immature DCs selectively express plenty of endocytosis receptors, such as Fcγ receptors(FcγRs), mannose receptor(MRs), and heat shock protein receptors, which could be used to target antigens for processing and presentation in vivo [8].
Fcγ receptors(FcγRs), a family of endocytotic receptors for the Fc portion of immunoglobulin, confer the protective effects of the immune system by recognition of IgG bound pathogens and play a critical role in autoimmune diseases [76]. Both human and mouse immature DCs express several FcγRs, and the activating
FcγRs(FcγR and FcγRⅢ) enhanc DC activation via immunoreceptor tyrosine-based activation motif (ITAM) ,while the inhibitory FcR (FcγR ) regulates DC function to promote Treg induction but inhibit effector T cell responses via immunoreceptor tyrosine-based inhibitory motif (ITIM) [77, 78]. Prior studies suggest that activating FcγR(FcγR and FcγRⅢ) deficiency protects from autoimmune diseases, such as arthritis and lupus [79]. TG19320, a tetrameric peptide interfere with IgG/FcγR interaction, attenuates kidney damage and prolongs the survival rate of lupus-prone MRL/lpr mice [80]. Moreover, mouse anti-human FcγRⅢ mAb 3G8 has been used to successfully treat immune thrombocytopenia (ITP) [81, 82]. Conversely, inhibitory FcR(FcγR Ⅱ ) suppresses the expression of proinflammatory cytokines of DCs stimulated by toll-like receptor (TLR) 4 via lipid kinase phosphoinositied 3-OH kinase(PI3K)/AKT signaling pathway [83]. And FcγR Ⅱ -overexpressing DCs dramatically prevents glomerulonephritis and enhances the survival rate of lupus-prone MRL/lpr mice [84]. Additionally, FcγRⅡspecific small chemical entities suppress arthritis development in a collagen-induced arthritis(CIA) model, an suppressive effect even stronger than methotrexate(MTX), a classical drug for RA in human [85]. Currently, FcγRs are appealing targets in the treatment of inflammatory autoimmune diseases. Targeting approaches include blocking activating FcγR and activating inhibitory Fc γ RⅡ.
DEC205 is an endocytotic receptor and highly expressed on several subsets of DCs [86]. Accumulating evidence suggests that DEC205 plays an important role for the induction of immunity and tolerance [87]. Prior studies have suggested that selective delivery of antigens to DEC205 on steady-state DCs confers a powerful method to induce antigen-specific T cell tolerance [88]. And recombinant anti-DEC205 Abs fused to disease-relevant autoantigens have been developed and used successfully for tolerogenic protection from autoimmunity in mouse models of autoimmune diabetes, encephalomyelitis and arthritis [89-91].
Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a typeⅡC-type lectin receptor that is abundantly expressed on DCs, especially immature DCs. Apart from being an adhesion molecule, DC-SIGN has emerged as a key player in the regulation of immune responses by recognition with several endogenous and exogenous antigens [92, 93]. As DC-specific phenotypic marker, DC-SIGN commonly recognizes intestinal commensal, which promotes DC induced generation of Tregs and prevents the development of T cell-dependent colitis [94]. Hence, DC-SIGN maybe a potential and valuable target on DC endocytosis in autoimmunity.
2.3 DC maturation in autoimmunity DCs are specialized sentinels responsible for coordinating innate and adaptive immunity. DC function is dependent upon their sensitivity to environmental inflammatory signs that promotes cellular maturation, phenotype alteration, activation and migration. We now appreciate that various molecules, signals, and mechanisms control the maturation of steady-state DC. Corruption of these steady-state operatives has diverse immunological consequences and pinpoints DCs as potent therapy targets of autoimmune diseases [95]. 2.3.1 Pattern recognition receptors Pattern-recognition receptors (PRRs) consist of Toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), and retinoic acid–inducible gene (RIG)-I-like receptors (RLRs) [95, 96]. Although best known as probes employed by DCs to sense pathogens and other environmental stimuli, many PRRs also transduce potent DC maturation signals and play a critical roles in autoimmunity.
Toll-Like Receptors(TLRs) are ligand-dependent detection modules that facilitate key aspects of innate and adaptive immunity. TLR signals within DCs are critical for induction of immune responses, with some exceptions given the nature of the
immunogens. Multiple lines of evidence indicate that activating TLR signals induce DC phenotypic and functional maturation and systemic autoimmunity [97]. Psoriasis in human patients is associated with upregulation of host molecules that enhance nucleic acid sensing by TLRs of plasmacytoid dendritic cells (pDCs) [98]. Duplication of the TLR7 gene causes DC expansion, maturation, and systemic autoimmunity. TLR9 over expression to the cell surface of hematopoietic stem cells (HSCs) results in CD11c+ DC expansion and activation, which induces the secretion of multiple pro-inflammatory cytokines (TNF-α, IL-1β) and fatal inflammation in irradiated mouse recipients. Anti-malarial drugs chloroquine and hydroxychloroquine that have been widely used in treatment of autoimmune diseases block DC activation through TLR7 and TLR9 [99, 100]. Myeloid differentiation factor 88(MyD88), the common TLR adaptor, mediates activation of peripheral myeloid dendritic cells and directs differentiation of T cells toward autoimmune Th17 cells [101]. MyD88 deficiency protects MRL.Faslpr mice from systemic lupus erythematosus (SLE), which is associated with down-regulation of expansion, activation, and cytokine secretion by DCs [102]. However, not all TLR signals induce DC maturation and autoimmune responses. Certain microbial products (e.g yeast zymosan, yersinia pestis, schistosomamansoni, bordetella pertussis) promote unexpected tolerogenic responses in DCs by binding TLR2, TLR4 or TLR6 [103]. The mechanisms that commensal sampling by DCs confers protection from autoimmune diseases and the intracellular signaling cascades that drive those tolerogenic DC functions require further investigation. Therefore, TLRs and their agonists maybe another potential targets for the treatment of autoimmune diseases.
C-Type Lectin Receptors (CLRs) are a variety family of transmembrane molecules containing the C-type lectin protein domain that enables binding of Ca2+ or carbohydrate ligands of commensal sampling. In most cases, CLRs down-regulate DC functions. For example, BDCA-2-Syk signals in human pDCs restrict interferon (IFN)-α
production
[104,
inhibition motif (ITIM)-containing
105]. CLRs
Immunoreceptor tyrosine-based that
activate
Src-homology
phosphatase(SHP) phosphatases can transduce negative maturation signaling in DCs. SHP-1 deficiency specifically up-regulates the expression of co-stimulatory molecules and MHC class
on DCs and leads to autoimmunity [106, 107]. Dendritic cell
immunoreceptor 1(DCIR1) is the only CLR whose genetic deletion in mice elicits spontaneous
autoimmune
disease
and
break
of
immune
homeostasis.
DCIR1-deficient mice develop IgM rheumatoid factor and antinuclear antibodies by 4-6 months of age, and arthritis develops in 30% of mice. In monocyte-derived DCs deprived from human, DCIR inhibits TLR-induced cytokine production [108, 109]. Those potential roles of CLR ligands in DCs may constitute an exciting prospect that may yield disease modulatory treatments with therapeutic value in autoimmune diseases.
Nucleotide oligomerization domain-like Receptors(NLRs) NLRs are cytoplasmic receptors that use their caspase recruitment domains to activate NF-κB or inflammasome to control the production of IL-1β and IL-18 [110, 111]. Nucleotide oligomerization domain (Nod) 2, which recognizes bacterial peptidoglycans, regulates some aspects of DC biology [112]. In graft versus host disease (GVHD), Nod2 knockout-DCs show enhanced phenotypic and functional maturation [113]. And Nod2 deficiency in mice displays gain-of-function and increased inflammatory cytokine secretion in DCs that causes increased susceptibility to DSS colitis [114]. These findings indicate a potential value for down-regulated DC Nod2 signals in the pathogenesis of autoimmune disease. Collectively, those potential mechanisms add intrigue to our understanding of the identity of PRRs. As the steady-state functions of those receptors may confer protection from autoimmune diseases, further pharmalogical development may constitute an exciting future with therapeutic value [115]. 2.3.2 Transcription factors Transcription factors, such as nuclear factor-kappa B (NF-κB), class O of forkhead box transcription factor(Foxo)3 and T-bet, potently manipulate DC phenotypic and functional maturation via upstream activating signals, and also play
critical role in autoimmunity. NF-κB is a signal transduction pathway molecule crucially involved in the inflammatory responses. Previous study reported that a common feature of drugs targeting DCs was their capacity to inhibit NF-κB, such as corticosteroids [12], CsA [73, 74], vitamin D3 analogs [35]. The NF-κB family member RelB is required for myeloid DC differentiation, and controls DC function via regulation of CD40 and MHC class II molecule expression [35]. Whereas another NF-κB family member NF-κB1, crucial for maintaining the resting state of DCs, restricts DC production of TNF-α [116, 117]. NF-κB inhibitor Bay11-7082 suppresses both CD40 and MHCⅡ expression and cytokine production on NiSO4 stimulated DCs [118, 119]. Bay11-7082 treated DCs prevent the development of collagen-induce arthritis (CIA) and inhibit CII specific T lymphocyte proliferation and antibody production [120]. Currently, a phase I clinical trial with tolerogenic DCs generated with Bay11-7082 is carried out in patients with RA. It has been found that DCs modified by Bay11-7082 were well tolerated and no major adverse effects were observed in this trial [121]. FOXO3, a member of Foxo family, was previously reported to play critical roles in
DC
function
through
a
“reverse
signaling”
process
mediated
cytotoxic T lymphocyte-associated antigen-4
(CTLA-4)
interaction
with
by B7
molecules resulting in increased indoleamine 2,3-dioxygenase (IDO) levels [95]. And siRNA-silenced Foxo3 expression leads to a decrease of DC tolerogenicity and expression of suppressive factors transforming growth factor (TGF)-β, and a concomitant increase in expression of CD80 and IL-6 [122]. And Foxo3 deficiency in steady state leads to 2-fold cellular expansion of splenic DCs and modest up-regulation of CD80 and CD86 in DCs [123]. Also Foxo3 restricts DC production of IL-6 and to a lesser extent of TNF-α and CCL2 [124]. In autoimmunity, prior study reported that Foxo3 activity was a predictive indicator of disease severity in Crohn's disease (CD) and rheumatoid arthritis [125]. And genetic manipulation in Foxo3 led to milder CD and lesser inflammatory responses, and was also associated with a milder course of RA but with increased susceptibility to more severe malaria [126]. In summary, those data suggest that Foxo3 may be part of the regulatory mechanisms
that program DC maturation and immune responses and can be a useful target in immune based therapies. T-bet is a transcription factor mostly noted for its role in T effector cell differentiation, but its role in DCs seems negative. The effect of T-bet on DC immunobiology depends mainly on the relationship between T-bet-mediated suppression of DC-produced TNF-α and TNF-α-dependent progression of colitis. T-bet-deficiency in DCs confers TNF-α over-express and triggers spontaneous ulcerative colitis with progressive development to colorectal cancer. And patients suffering inflammatory bowel disease are often successfully treated with anti-TNF-α therapy [127-129]. 2.3.3 Immune mediators DC maturation encompasses the down regulation of endocytic capacity, the up-regulation of surface T-cell co-stimulatory (CD40, CD80 and CD86) and MHC class II molecules, the production of bioactive pro-inflammatory cyokines such as IL-12, TNF-α and IL-6 and the inhibition of anti-inflammatory cyokines such as IL-10 and TGF-β. These immune mediators control steady-state DC maturation and disruption of these factors leads to diverse immunological consequences and pinpoints DCs as potent drivers of autoimmune disease. Thus, targeting on these immune mediators may result in therapeutic values in autoimmune diseases. Most anti-inflammatory and immunosuppressive mediators suppressed immune responses are coupled with inhibition in DC phenotypic and functional maturation. These mediators include immunosuppressive drugs such as corticosteroids [12, 13], vitamin D3 [14-17], rapamycin [23-27], CsA [73, 74], tacrolimus [130], aspirin [28-30], mycophenolate [32, 33], sanglifehrin A [131], leflunomide [132], intravenous immunoglobulin(IVIG) [133] rosiglitazone [37, 38] and troglitazone [18]; the mucolytic antioxidant N-acetyl-L-cysteine [31]; anti-malarial drugs such as chloroquine and hydroxychloroquine [134, 135]; pro-inflammatory factor blockers such as TNF-α blocker (adalimumab [136], infliximab [137]), and IL-6 blocker(tocilizumab [138]); anti-inflammatory factors such as IL-10 [139-144],TGF-β [145-148]; vascular endothelial growth factor (VEGF), PGE2, retinoids, HLAG,
flavonoid [9, 35, 103, 149-151], and several Chinese herbal medicine and their components [41, 72, 132] [152](for detail seen Tab.1) Co-stimulatory and MHC class II molecules
DCs have a dual ability to either
activate or suppress immunity, which is mainly associated with the expression of co-stimulatory and MHC class II molecules [153]. In addition to chemical or tissue culture induced tolerogenic DCs, genetic engineering methods can also be used for the creation of tolerogenic DCs. Recent studies indicate that gene silencing of CD40, CD80,and CD86 through administering short interfering RNA (siRNA) achieves optimal protection from disease and induced antigen-specific Tregs in CIA mice [154, 155]. Apart from co-stimulatory molecules, MHC class II molecules are indispensable for DC immune biology. In the steady state, MHC class II molecules connect with a single lysine by ubiquitin chains. And once DC activated, deubiquitination will happen in MHC class II molecules, which leads to accumulation of MHC class II on DC cell surface [155-158]. Thus, blocking the deubiquitination and maintaining ubiquitination of MHC class II will be a potential target on preventing immune responses in autoimmune diseases. The ubiquitin-conjugating molecule MARCH1 is primarily expressed in immature DCs, and has the effect to down regulate DC activation. MARCH1-deficient DCs express 10- fold higher levels of MHC class II molecules and CD86, but with significantly reduced cytokine responses to LPS and CD40 ligand and diminished capacity to present MHC class II restricted antigens [156, 159]. The mechanisms and significances of the contradictory effects of MARCH1-deficient DCs require further investigated. Collectively, those data offer a new insight in targeting DC phenotypic maturation to manipulate the treatment of autoimmunity. Cyokines. Once activated, DCs undergo functional maturation and produce multiple cytokines, including pro-inflammatory cytokines such as TNF-α, IL-6, IL-12 and IL-1β, and anti -inflammatory cytokines such as IL-10, TGF-β [1, 160]. Those cytokines play critical roles in autoimmune responses. As the products of DCs, they also induce the differentiation of immature DCs into mature DCs that can instruct naive T cells differentiating toward Th1, Th2, Th17 or Treg cells [160]. Due to their
potential on regulating the balance between immunity and tolerance, the bioavailability of those cytokines and their effect on DC functions have been implicated in inflammatory and autoimmune diseases. Currently, biological agents targeting on cytokines TNF-α, IL-6 and IL-1 are widely used in autoimmune diseases, such as RA, Crohn’s disease, psoriatic arthritis (PsA), and ankylosing spondylitis(AS) [161-167]. This represents a success of immunology in clinical application and the coming years will witness the expanding benefit of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology. Apart from pro-inflammatory cytokines, anti-inflammatory cytokines IL-10, TGF-β directly targeting on DC functions, are powerful tolerogenic agents which induce tolerogenic DCs to secrete even higher levels of anti-inflammatory cytokines. IL-10 interferes with differentiation of peripheral blood monocytes to DCs and induces cells with a tolerogenic phenotype [168]. Addition of IL-10 to differentiation cocktail induces a sustained inhibitory effect on subsequent maturation of monocyte-derived DCs And exogenous IL-10 reduced the expression of MHCⅡand CD80, decreased IL-12p40 level, and increased IL-10 level in DC, which resulted in impaired capacity to stimulate allogenic T-cell proliferation [169]. IT9302, a nonameric peptide homologous to the C-terminal domain of human IL-10, can promote monocyte differentiation to tolerogenic DCs through mechanisms involving STAT3 inactivation and NF-κB intracellular pathway blockade [170]. And IL-10 induced tolerogenic DCs were previously reported to prolong allograft survival by blocking the expression of CD80 and CD86, leading to apoptosis of allospecific T cells [171]. Similar to IL-10, TGF-β utilizes distinct pathways to reduce the expression of CD80 and CD86 by DCs and suppresses IL-12 production, giving rise to a reduced capacity to prime T cells [172]. Moreover, tolerogenic DCs stimulated by TGF-β delayed corneal allograft rejection by up-regulation the number of Foxp3+ Tregs [173]. And treatment of grafted β-cells islets with TGF-β-generated tolerogenic DCs prolonged graft survival [174]. Besides, genetic manipulation of DC maturation has allowed DC up-regulation of IL-10 and TGF-β that inhibit antigen presenting process. And those genetically programmed DCs display tolerogenic function through various mechanisms and some
of them even show therapeutic potential for graft rejection and autoimmune diseases [103]. 2.3.4 Other regulators Several other molecules have been found to intrinsically regulate DC maturation, and importantly, absence of any one of these regulators results in evident development of autoimmune diseases in mouse models. These intrinsic controllers have different protein characters, including αvβ8 integrin [175]; signal transducer and activator of transcription 3 (STAT3) [176] and A20 [95]. αvβ8 integrin expressed by DCs activates latent TGF-β and is critical for immune homeostasis [177]. Mice with DCs lacking αvβ8 and those lacking αvβ8 on all immune cells displayed similar pathologies of splenomegaly, lymphadenopathy, spontaneous T cell activation, autoantibodies, and colitis [175]. STAT3-mediated transcription was required to suppress activation markers on DCs [178]. Moreover, DCs can be categorized by the levels of cellular STAT3 phosphorylation/activation [178], the highest of which correlates with low expression of MHC class II. Thus, those molecules serve as ‘domestic police’ that inhibit DC dysfunction and the subsequent T cell disorder, and eventually contribute to the prevention of autoimmune diseases. A20, the product of the TNFAIP3 gene, restricts a number of innate immune signaling cascades that regulate DC functions, including TLR, NOD2, CD40, and TNF signals [179-181].
2.4 DC migration in autoimmunity The ability of DCs to initiate and orchestrate adaptive immune responses is a consequence of their localization within tissues and their specialized capacity for migration. Accumulating evidence indicates that trafficking molecule matrix metalloproteinases (MMPs) [182, 183], chemokines and their receptors [184] and adhesion molecules [185] play critical roles in orchestrating DC migration. Once a mobilization signal has triggered detachment from parenchymal tissues, maturing DC secrete MMPs to disintegrate extracellular matrix (ECM) barriers. Then under the regulation of chemokines and adhesion molecules, DCs traffic to secondary lymphoid organs to present the antigen to T cells and elicit the adaptive immune responses, and
consequently result in autoimmune diseases. Hence, pharmacological inhibition on DC migration will contribute to the prevention of autoimmune diseases. Prior studies have reported that pharmacological effects on DC migration can be achieved by immunomodulatory agents, including immunosuppressant such as corticosteroids [34, 186], vitamin D3 [34], CsA [34, 73, 74], mycophenolate [187] and leflunomide [188, 189]; Chinese herbal medicine such as triptolide [190], apigenin [191] and quercetin [75]; cytokines such as IL-10 [192], IL-21 [193], M-CSF [194]. These agents modulate DC migration primarily via control of trafficking molecules. Here, we review the key molecular traffic signals that govern the migration of DCs and provide novel insights into the significance of DC migration in the treatment of autoimmune diseases.
2.4.1 Matrix metalloproteinases Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9 serve to disintegrate extracellular matrix(ECM) barriers, such as collagen types I-IV, fibronectin, and laminin [182, 195], which enables DCs to traffick through interstitial space to afferent lymph vessels. MMPs have been found to be key molecules in DC migration. Neutralizing or suppressing antibodies to MMP activity inhibits DC migration in Matrigel assays as well as langerhans cell(LC) emigration from skin explants [196, 197]. And MMP-9-deficient DCs in vitro are markedly defective in transepithelial migration and move poorly to LNs in vivo [198]. Inhibitors of metalloproteinases (TIMPs) and endogenous regulators of MMP activity have been suggested to block interstitial DC migration [182]. Furthermore, previous study showed that over-expression of genes encoding MMPs, such as MMP-1, -10 and -12 correlated with enhanced migratory capacity of DCs measured in Matrigel assays [199]. Besides, studies have suggested that MMPs(especially MMP-9) play a critical role in autoimmune disease. Over production of MMP-9 have been found in the sera and synovial fluid (SF) from patients with RA [200]. And the increased level of MMP-9 activity in the synovial fluid of RA and the severity of the disease has been correlated [201]. MMP-9 deficient mice showed inhibition of the development of
antibody-induced arthritis, one of the murine models of RA. The mechanisms that MMP-9 promote arthritis development may result from the effect of MMP-9 on migration of inflammatory cells, such as DCs [202]. Those findings indicate a potential role of MMPs in DC migration in the pathogenesis of autoimmune diseases and pharmacological inhibition on MMPs may constitute an exciting future for the treatment of autoimmune diseases. 2.4.2 Chemokines and the receptors Chemokines are small-secreted chemotactic cytokines that regulate the migration of leukocytes under steady state and inflammatory conditions. The migratory pathway of DCs start with recognition of a mobilizing signal induced by a variety of maturation factors, such as IL-1β, TNF-α and LPS [203]. Administration of these molecules leads to the loss of DCs from the periphery within a few hours. Pharmacological inhibitors or neutralizing antibodies of IL-1β or TNF-α impair mobilization and migration of DCs [203, 204]. Corticosteroids inhibit DC migration to lymphoid tissues through suppressing the inflammatory cytokine production. DC activation initiates a significant change in the repertoire of chemokine receptors (CCRs) [186]. The dominant chemokine pathway for DC migration to lymph nodes via lymphatics is CCR7 and its ligands, CCL19 and CCL21. CCR7-deficient mice show defective DC migration to LNs, which results in fewer putative migratory DCs in LNs after contact sensitization [205, 206]. Mobilizing signal induced by TNF-α significantly up-regulates the expression of CCL21 secreted by lymphatic endothelial cells, thus making the reactive vessels even more attractive to migrating DCs [207, 208]. Neutralizing antibodies to CCL21 has been suggested to inhibit the migration of skin-derived DCs into skin-draining LNs [209]. The cyclophilin-binding agent sanglifehrin A can suppress DC migration by suppressing CCL5, CCL17, CCL19, CXCL9 and CXCL10 expression in human monocyte-derived DCs [210]. IFN-β inhibits DC migration through STAT-1–mediated transcriptional suppression of CCR7 [211]. Chinese herbal derived immunosuppressive medicine triptolide impairs DC migration by inhibiting CCR7 and COX-2 expression [190] . Some flavonoid compounds like quercetin and apigenin can also inhibit DC migration through
down-regulation of chemokines and their receptors [75, 191]. Several other chemokine receptors play a role in DC traffic from the periphery to draining lymph nodes but appear less important. Migration of plasmacytoid DCs (pDCs ) activated with CpG for 24 h from peripheral blood into the lymph nodes has been indicated to depend on the CXCR3 and ligand CXCL9 [212]. CXCR4 inhibition impairs migration of LCs and dermal DCs to draining LNs [213]. Moreover, emigration of skin-DCs and lung-DCs [214] to the draining lymph node was partially blocked in CCR8-deficient mice. Hence, chemokine receptors are essential in lymph node homing of endogenous DCs. And pharmacological therapy on DC migration may target on down-regulation the expression of chemokine receptors on DCs or local chemokine expression. 2.4.3 Adhesion molecules In addition to acquiring the capacity to across ECM barriers, maturing DCs must develop the ability to entry into lymphatic system. Accumulating evidence indicates that multiple traffic molecules play a role in DC migration through the lymphatic system [4]. The best-validated molecules for DC migration into afferent lymphatics are adhesion molecules. After pro-inflammation-cytokine stimulation, lymphatic endothelial cells up regulate adhesion molecules and form tight and adherens junctions, resulting in DC trafficking within the afferent lymphatics [215, 216]. The key adhesion molecules for DC migration included selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and their respective receptors [216]. Related study showed that antibody neutralization or suppression on VCAM-1 and ICAM-1expression can block DC adhesion to lymphatic endothelium and migration into afferent lymph vessels both in vitro and in vivo [217, 218]. And ICAM-1 deficiency mice also showed impaired langerhans cell migration to lymph nodes(LNs) [219]. P-selectin glycoprotein ligand-1 (PSGL-1) is the ligand for P-selectin and highly expressed on DCs. Prior study suggests that antibody against PSGL-1 block DC migration into LNs [220]. Similarly, integrin α6 is upregulated and contributes to migration of LCs [221]. Currently, the inhibition of adhesion molecules has been found to prevent or ameliorate disease severity in animal
models and clinical studies [216, 222]. Treatment with anti-ICAM-1 monoclonal antibody(mAb) have been found to reduce the severity of collagen- induced arthritis in mice and adjuvant induced arthritis in rats and to prolong the survival of cardiac allografts in mice [222-224]. Whereas pre-clinical studies of an antisense oligonucleotide to human ICAM-1 in Crohn’s disease and RA demonstrated no significant differences in disease severity between the placebo and treated patients [216, 225]. Similarly, related studies showed that anti-E-selectin mAb treatment protected against adjuvant-induced arthritis and colitis in animal models [216, 226], but not effective in the treatment of psoriasis in a randomized clinical trial [227]. However, not all the adhesion blockade studies show disappointing results. The anti-CD11a (the receptor of ICAM-1) mAb, efalizumab, has shown promising results in psoriasis patients. And the anti-α4 mAb, natalizumab, has proven to be safe and efficacious in patients with multiple sclerosis [228] or Crohn’s disease [229]. Taken together, adhesive interaction is a most important aspect of DC migration and understanding the underlying mechanisms may provide new potential therapeutic targets to modulate immune responses in autoimmune diseases. 2.4.4 S1P and receptors Sphingosine-1-phosphate (S1P), a potent bioactive sphingolipid metabolite that regulates many cellular processes including cell survival, cytoskeletal rearrangements, cell migration, and production of cytokines and chemokines , is involved in many kinds of diseases such as atherosclerosis, cancer, asthma and autoimmune diseases [230, 231]. S1P and its receptors also play a role in the interstitial migration of fully differentiated DCs. The novel immune-modulator FTY720 is a chemical derivative of myriocin, and its phosphorylated metabolite FTY720-P is a structural homolog of S1P. FTY720 inhibits S1P function through internalizing of S1P receptors, making cells unresponsive to S1P [232]. Researchers have demonstrated FTY720 could alleviate the clinical signs of experimental asthma, allergic contact dermatitis, and skin allograft transplantation through impairing DC trafficking to draining LNs [233-235]. Our recent study showed that FTY720 treatment also significantly suppressed the incidence and severity of collagen-induced arthritis (CIA) in DBA/1J mice via the
modulation of DC migration. CCR7 down-regulation on DCs and decreased CCL19 secretion are responsible for the impairment of DC migration by FTY720. The results indicate inhibition on migration by FTY720 may provide a novel approach in treating autoimmune disease such as RA[236]. And FTY720 has been shown to be a useful agent for the prevention of transplant rejection and has been proved by FDA to treat MS [237]. 2.4.5 Others molecules Factors present in inflammatory sites, such as lipid mediators, particularly prostaglandin E2 (PGE2) [238], and the high mobility group box-1 (HMGB1) protein [239], have been shown to induce migration of maturing DCs. The role of PGE2 in DC migration is strongly supported by the fact that mice deficient in the PGE2 receptor EP4 or wild-type mice treated with an EP4 antagonist exhibit reduced DC migration to lymph nodes [240]. The PGE2-induced DC migration is mediated through up-regulates MMP-9 expression, including both secreted and membranebound MMP-9 [183]. Besides, Faure-Andre and colleagues recently noted that DC migration was regulated by Ii, a key intracellular chaperone of MHC class II molecules that directs MHC class II endosomal localization and enables peptide loading. Ii-mediated association and activation of myosin light chain, which mediates cell migration, may enable DCs to effectively probe the tissue microenvironment [241]. DCs express cannabinoid receptor 2 (CBR2) and CBR2 agonists decrease autoimmune inflammation and DC production of pro-inflamamtory cytokines and capacity to stimulate CD4+ T cells. CBR2 agonists were found to inhibit DC migration from peripheral tissues by blocking MMP9 expression [242] .
3. Conclusion As the most powerful APC, DCs serve as the key bridge between innate and adaptive immunity. DCs also function as a critical switcher between immune activation and immune tolerance. To be a truly effective immune system manipulator, DCs must endure many steps of evolution. And each step was regulated subtly by a
variety of molecules. These steps, from differentiation, endocytosis to maturation and migration, are closely associated with the function of DCs and the outcome of immune response. Impaired endocytosis of dead cells by DCs is implicated in the pathogenesis of SLE; Different DC maturation state determines the immune system to be activated or tolerant; Migration is the prerequisite step for DCs to intact with T cells/B cells in LNs and orchestrate them subsequently. The complexity of DC evolution process and the flexibility of their property determine the biological basis of their variety functions and the ability to react with different environments efficiently. And also provide us with plenty therapeutic targets to manipulate them. Further studies in the mechanisms of current drugs or novel molecules in DC functions will be of great significance for developing unpreceding protocols for the treatment of autoimmune diseases.
Conflict of interest The authors have no conflict of interest. Acknowledgments We thank the many researchers who have contributed to our current understanding of DC functions. This work was supported by grants from National Natural Science Foundation of China (Grant No.81202359，81471613)
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Figure legend Fig. 1. Targeting dendritic cell (DC) functions for treatment of autoimmune diseases. After generated from haematopoietic stem cell in the bone marrow, DCs are generally immature and traffic to the peripheral tissues, where they undergo several molecular events, namely differentiation, endocytosis, phenotypic and functional maturation, migration to the secondary lymphoid organs and present acquired antigens to naive T lymphocytes. And each event was regulated subtly by various molecules, signals, and mechanisms. HSC, haematopoietic stem cell; iDCs, immature dendritic cells; mDCs mature dendritic cells; LNs, Lymph nodes; ECM, extracellular matrixc, ECM.
Table 1. Representative immunomodulatory targets and their effects on DC functions. Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
[12, 22]
Study Differentiation
Dexamethasone
human
moDCs
in vitro
low levels of CD1a
Phenotypic
Cytokine
Migration
T Cell
maturation
production
MHC-II↓
TNF-α↓
CCL3↓
Less Th1/Th2
Immune-mediated diseases
stimulation
And other
CD40↓
IL-12↓
CCL2↓
cell generation,
Corticosteroids
CD86↓
IL-1β↓
CCL5↓
More Treg cell
CCL28↓
generation
CD54↓
CCL22↓ Vitamin D3
mouse
human
Dexamethasone +
mouse
BMDCs
moDCs
BMDCs
in vivo
in vitro
in vitro
(-)
low levels of CD1a
(-)
Vitamin D3
MHC-II↓
TNF-α↓
CCL3↑
More Treg cell
EAE,
CD80↓
IL-10↑
CCL2↑
generation
Autoimmunity
MHC-II↓
IL-10↑
CCL5↓
Less Th1/Th2
MS,
CD40↓
IL-12↓
CCL18↑
cell generation,
Autoimmunity
CD83↓
TNF-α↓
CCL22↓
More Treg cell
CD86↓
IL-6↓
[13, 14]
[15]
generation
MHC-II↓
IL-12↓
ICAM-1↓
Inhibit
CD40↓
INF-γ↓
CCL3↑
stimulation,
diseases
CD80↓
CCL2↑
CD86↓
CCL5↓
T-cell
Immune-mediated
[19,22]
CCR1,2,5,7↓ human
moDCs
in vitro pre-clinical
(-)
MHC-II↓
IL-10↑
Inhibit T-cell
graft rejection;
CD40↓
IL-12↓
stimulation,
Rheumatoid
CD83↓
TNF-α↓
arthitis; Sjogren
CD86↓
IL-6↓
syndrome
[16-21]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
[21]
Study Differentiation
Phenotypic
Cytokine
maturation
production
Migration
T Cell stimulation
MHC-II↓
IL-10↑
Less Th1
Rheumatoid
Dexamethasone
CD40↓
IL-12↓
cell generation,
arthritis;
+monophosphoryl
CD80↓
TNF-α↓
More Treg cell
Immune-mediated
lipid A
CD83↓
IL-23↓
generation
diseases;
human
moDCs
in vitro
(-)
CCL19↓,
Prevention of graft
CD86↓
rejection Rapamycin
mouse
BMDCs
in vitro
GM-CSF↓,
MHC-II↓
IL-12↓
IL-4R↓,
CD40↓
TNF-α↓
FLT3L↓
CD80↓
(-)
More Treg cell
Prevention of graft
generation
rejection
Reduce survival
Prevention of graft
of alloantigen
rejection
[23-25]
CD86↓ mouse
BMDCs
in vivo
(-)
(-)
(-)
(-)
[26]
specific CD8+ T cells human
moDCs
in vitro
(-)
CD40↓
(-)
(-)
CD80↓
More Treg cell
Immune-mediated
generation
diseases
[27]
CD86↓ Sanglifehrin A
human
moDCs
in vitro
(-)
(-)
IL-12↓ IL-23↓
(-)
(-)
Immune-mediated diseases
[131]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Inhibit T-cell
Immune-mediated
[74]
TNF-α↓
stimulation
diseases
IL-12↓
Lower Th1
Immune-mediated
TNF-α↓
cell generation,
diseases
Study Differentiation
Cyclosporin A
mouse
human
BMDCs
moDCs
in vitro
in vitro
(-)
(-)
Phenotypic
Cytokine
maturation
production
(-)
IL-12↓
(-)
Migration
T Cell stimulation
CCR7↓
[73]
More Treg cell generation Mycophenolate
mouse
BMDCs
in vitro
(-)
CD40↓
IL-12↓
ICAM-1↓
CD80↓
Inhibit T-cell
Immune-mediated
stimulation
diseases
[32]
CD86↓ human
Tacrolimus
mouse
moDCs
BMDCs
in vitro
in vivo
(-)
(-)
CD54↓
IL-10↓
Inhibit T-cell
Immune-mediated
CD80↓
IL-12↓
stimulation
diseases
CD83↓
TNF-α↓
CD86↓
IL-18↓
(-)
(-)
More Treg cell
CIA
[130]
More Treg cell
Rheumatoid
[130]
generation
arthritis
More Treg cell
CIA
generation
MS
(-)
(FK-506)
[33]
generation human
moDCs
in vitro
(-)
MHC-II↓
TNF-α↓
CD40↓
IL-10↑
(-)
CD80↓ CD86↓ FTY720
mouse
BMDCs
in vivo
(-)
(-)
IL-12↓
CCR7↓
[236, 237]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Inhibit T-cell
Immune-mediated
[134, 135]
stimulation
diseases
(-)
Immune-mediated
Study Differentiation
chloroquine
mouse
BMDCs
in vitro
(-)
Phenotypic
Cytokine
maturation
production
CD80↓
IL-10↓
CD86↓
IL-12↓
Migration
T Cell stimulation
(-)
TNF-α↓ Aspirin
human
moDCs
in vitro
(-)
CD83↓
IL-10↓
(-)
IL-12↓
[30]
diseases
TNF-α↑ mouse
Butyric acid
human
BMDCs
moDCs
in vitro
in vitro
promoted the
MHC-II↓
generation of CD11c+
CD40↓
DC;Phagocytosis
CD80↓
inhibition;
CD86↓
Differentiation
MHC-II↓
Inhibition;
CD40↓
reducing the phagocytic
CD86↓
capacity
CD83↓
IL-12↓
(-)
(-)
(-)
Inhibit T-cell
Immune-mediated
stimulation
diseases
Inhibit T-cell
Immune-mediated
stimulation
diseases
Inhibit T-cell
Immune-mediated
stimulation
diseases
Reduce T cell
Type-1 Diabetes
[28, 29]
[36]
CD86↓ N-acetyl-L-cystei
human
moDCs
in vitro
ne
(-)
MHC-II↓
IL-12↓
CD40↓
IL-6↓
CD86↓
IL-8↓
(-)
[31]
TNF-α↓ Troglitazone
human
moDCs
in vitro
(-)
priming
[17]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
Autoimmunity;
[37]
priming
EAE Type-1 Diabetes
[38]
Immune-mediated
[132]
Study Differentiation
Rosiglitazone
mouse
BMDCs
in vitro
(-)
Phenotypic
Cytokine
maturation
production
(-)
(-)
Migration
T Cell stimulation
(-)
human
moDCs
in vitro
CD1a↓
CD80↓
(-)
(-)
Reduce T cell
human
moDCs
in vitro
(-)
CD80↓
(-)
CCR7↓
(-)
priming leflunomide
CD86↓ Triptolide
Apigenin
human
mouse
mouse
moDCs
BMDCs
BMDCs
in vitro
in vitro
In vivo
CD1a↓
(-)
(-)
diseases
MHC-II↓
IL-12↓
CCR7↓,
Reduce T cell
Immune-mediated
CD40↓
TNF-α↓
CCR5↑,
priming;
diseases
CD80↓
IL-10↓
COX-2↓,
More Treg cell
CD86↓
TGF-β↓
MHC-II↓
IL-12↓
CD40↓,
TNF-α↓
CD80↓,
IL-10↓
CD86↓,
IL-1β↓
MHC-II↓
TNF-α↓
CD40↓
IL-6↓
CD80↓
IL-1β↓
[190]
generation CXCR4↓
(-)
(-)
[191]
CXCR4↓
(-)
CIA
[191]
[75]
CD86↓ Quercetin
mouse
BMDCs
in vitro
reducing the phagocytic
MHC-II↓
IL-12↓
CCL3↓
Reduce T cell
Immune-mediated
capacity
CD40↓
TNF-α↓
CCL2↓
priming
diseases
CD80↓
IL-10↓
CCL5↓
CD86↓
IL-1β↓
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
EAE
[151]
EAE
[72]
[242]
Study Differentiation
Chrysin
human
moDCs
In vivo
(-)
Phenotypic
Cytokine
maturation
production
MHC-II↓
IFN-γ↓
CD83↓
IL-12↓
Migration
T Cell stimulation
(-)
Less Th1 cell generation,
CD86↓
More Treg cell generation
Fumarates
mouse
BMDCs
in vitro
(-)
(-)
IL-12↓
More Treg cell
More Treg cell
IL-23↓
generation
generation
(-)
Reduce T cell
Immune-mediated
priming;
diseases
Reduce T cell
rheumatoid
priming;
arthritis;
IL-10↑ Auranofin
mouse
BMDCs
in vitro
inhibition of the
MHC-I↓
phagocytic activity of
MHC-II↓
(-)
DCs Rabeximod
human
moDCs
in vitro
CD1a↓,
MHC-I↓
IL-6↓
(-)
MHC-II↓
n-3 fatty acid
human
moDCs
in vitro
CD1a↓,
CD80↓
Immune-mediated
CD40↓
diseases
(-)
IL-6↓
(-)
(-)
Immune-mediated
[39]
[40]
diseases Glatiramer acetate
mouse
BMDCs
In vivo
(-)
(-)
IL-10↑
CCL2↓ CCL3↓ CCL5↓ IP-10↓
(-)
EAE
[152]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
Immune-mediated
[133]
priming;
diseases,
Study Differentiation
IVIg
human
moDCs
in vitro
CD1a↓
Phenotypic
Cytokine
maturation
production
MHC-II↓
TNF-α↓
CD83↓
IL-12↓
CD86↓
IL-10↑
Migration
T Cell stimulation
(-)
transplantation
CD40↓ Bay 11-7082
human
(NF-κB inhibitor)
human
in vitro
(-)
umbilical
CD83↓
IL-8↓
(-)
(-)
CD86↓
Immune-mediated
[121]
diseases
cord blood-DCs mouse
BMDCs
In vivo
(-)
(-)
(-)
(-)
Reduce T cell
CIA
[118-120]
Reduce T cell
SKG mice from
[243]
priming;
getting arthritis
response MHC-II↓
IL-6↓
(histone
CD40↓
IL-12↓
deacetylase
CD80↓
Trichostatin A
mouse
BMDCs
in vitro
(-)
mouse
BMDCs
In vivo
(Flt3 inhibitor) Oenothein B
Lupus
CD86↓
inhibitor) Sunitinib
(-)
Reduce CD11c+
(-)
(-)
(-)
(-)
population mouse
BMDCs
in vitro
CD1a↓,
antigen-induced
[49]
arthritis CD83↓
IL-6↓ IL-1β↓
(-)
(-)
inflammatory bowel disease, celiac disease, rheumatoid arthritis.
[244]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
rheumatoid
[137]
priming;
arthritis
Reduce T cell
rheumatoid
priming;
arthritis
Study Differentiation
Infliximab
human
moDCs
In vivo
(TNF-α blocker)
Less CD11c+ DCs
Phenotypic
Cytokine
maturation
production
(-)
Migration
T Cell stimulation
(-)
CD123+ DCs percentages
Tocilizumab
human
(-)
In vivo
(IL-6 blocker) Tofacitinib
reduction of circulating
(-)
IL-6↓,\
(-)
myeloid DCs human
moDCs
in vitro
(-)
CD80↓ CD86↓
IL-1β↓
mouse
BMDCs
in vitro
(-)
(-)
IFN-α↓
Chemokines
Reduce T cell
Immune-mediated
(spleen tyrosine
IL-2↓
IP-10↓
co-stimulator
diseases
kinase inhibitor)
IL-5↓
CCL3↓
(ICOS) and
( JAK inhibitor) Fostamatinib
IL-6↓
rheumatoid
[138] [245]
arthritis [246]
PD-1
IL-6↓ IL-13↓ IL-17↓ Vasoactive
mouse
BMDCs
in vitro;
endocytosis↑,
intestinal peptide
MHCⅡ↓
TNF-α↓
More Treg cell
Immune-mediated
CD40↓
IL-12↓
Generation, and
diseases
CD80↓
IL-6↓
Reduce T cell
CD86↓
IL-10↑
priming
(-)
[247]
CD83↓ TGF-β
mouse
BMDCs
In vivo
(-)
MHCⅡ↓
TNF-α↓
CD40↓
IL-12↓
CD80↓
IL-6↓
CD86↓
IL-1β↓
(-)
Reduce T cell
Type 1 Diabetes;
priming
Prevention of graft rejection
[146, 147]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
Systemic Lupus
[139-144]
priming;
Erythematosus;
Study Differentiation
IL-10
human
moDCs
Phenotypic
Cytokine
maturation
production
in vitro
CD1a↓,
MHC-Ⅱ↓
IL-12↓
pre-clinical
DC-SIGN↑,
MHC- ↓
IL-6↓
CD83↓
TNF-α↓
Migration
T Cell stimulation
CCR7↓
Type 1 Diabetes;
CD80↓
Immune-mediated
CD86↓
diseases; Asthma and allergy
rat
BMDCs
in vivo
(-)
CD86↓
(-)
(-)
Reduce T cell
Prevention of graft
priming and
rejection
[171]
allospecific T cell response mouse
BMDCs
(-)
MHCⅡ↓
IL-6↓
MHCⅠ↓
IL-12↓
B7-1↓
IL-23↓
(-)
Reduce T cell
delayed-type
priming
hypersensitivity
Reduce T cell
Anti-phospholipid
priming
syndrome;
[168]
B7-2↓ IL-10+TGF-β
human
moDCs
in vitro;
CD1a↑
pre-clinical
MHCⅡ↓
IL-12↓
CD40↓
IL-10↑
(-)
[145, 148]
Type 1 Diabetes
CD83↓ CD86↓ M-CSF
human
moDCs
in vitro;
CD1a↓,
MHCⅡ↓
TNF-α↓
CD40↓
IL-12↓ IL-10↑
CXCR4↓
Reduce T cell
Immune-mediated
priming
diseases
[248]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
Immune-mediated
[249]
priming
diseases
More Treg cell
EAE
Study Differentiation
IL-21
human
moDCs
in vitro;
endocytosis↑,
Phenotypic
Cytokine
maturation
production
MHCⅡ↓
TNF-α↓
CD80↓
IL-12↓
Migration
T Cell stimulation
CCR7↓
IL-6↓ IL-1β↓ TNF-α
IFN-β
mouse
mouse
BMDCs
BMDCs
In vivo
in vitro
(-)
(-)
CD40↑
IL-12↓
CD80↑
IL-6↓
Generation, and
CD86↑
IL-1β↓
Reduce T cell
IL-10↑
priming
CD40↑ CD80↑
(-)
(-)
CCR7↓
[250]
[251]
MMP-9↓
CD86↑
moDC, monocyte-derived DC; BMDC, bone marrow-derived DC; MHC II, major histocompatibility class II molecules; IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; TGF:transforming growth factor; ICAM, intercellular cell adhesion molecule; CIA: collagen-induced arthritis; EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis.
S1043-6618(16)30096-2 http://dx.doi.org/doi:10.1016/j.phrs.2016.02.023 YPHRS 3083
To appear in:
Pharmacological Research
Received date: Revised date: Accepted date:
5-2-2016 23-2-2016 23-2-2016
Please cite this article as: Li Xing, Han Yanping, Sun Erwei.Sniping the Scout: Targeting the key molecules in dendritic cell functions for treatment of autoimmune diseases.Pharmacological Research http://dx.doi.org/10.1016/j.phrs.2016.02.023 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Sniping the Scout: Targeting the key molecules in dendritic cell functions for treatment of autoimmune diseases
Authors: Xing Lia,b, Yanping Hanc and Erwei Suna,b,*
a Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China. b Institute of Clinical Immunology, Academy of Orthopedics·Guangdong Province, China. c Hospital of South China Normal University, Guangzhou, China.
* Address correspondence to Erwei Sun M.D., Ph.D.: Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Avenue West, Tianhe District, Guangzhou 510630, China. E-mail: [email protected], Tel：+86-20-682784421.
Abstract Dendritic cells (DCs) are a power tool for manipulating immune system. They play important roles in the induction of immunity as well as inducing intrathymic and peripheral tolerance. After generated from stem cells in the bone marrow, DCs traffic to the peripheral tissues, where they capture and process antigens, express lymphocyte co-stimulators, migrate to the secondary lymph organs and present the processed antigen to naive T cells to either activate or tolerize them. These processes are modulated subtly and influenced by various factors. Aberrant regulation of the processes may cause autoimmunity. Investigation into the biology of DCs and the molecules and mechanisms that regulate them helps us understanding the pathogenesis of autoimmune diseases and reveals numerous steps for pharmacological manipulation. In this review, we made a sketch line of the critical events of DC biology that are potential pharmacologic targets for the treatment of autoimmune diseases. Keywords: Autoimmune diseases; Dendritic cells; T helper ; Rheumatoid arthritis; Systemic lupus erythematosus; Chemical compounds studied in this article Dexamethasone (PubChem CID: 5743); Vitamin D3 (PubChem CID: 5280795); rapamycin (PubChem CID: 5284616); Aspirin (PubChem CID: 2244); N-acetyl-L-cysteine (PubChem CID: 12035); mycophenolate mofetil (PubChem CID: 5281078); Butyric acid (PubChem CID: 264); rosiglitazone (PubChem CID: 77999); Sanglifehrin A (PubChem CID: 5388925); Cyclosporin A (PubChem CID: 5284373); Tacrolimus (PubChem CID: 445643); FTY720 (PubChem CID: 107969); Chloroquine (PubChem CID: 2719); Troglitazone (PubChem CID: 5591); Leflunomide (PubChem CID: 3899); Triptolide (PubChem CID: 107985); Apigenin (PubChem CID: 5280443); Quercetin (PubChem CID: 5280343); Chrysin (PubChem CID: 5281607); Fumarates (PubChem CID: 5281069); Auranofin (PubChem CID: 24199313); Glatiramer acetate (PubChem CID: 3081884); Trichostatin A (PubChem CID: 444732); Sunitinib (PubChem CID: 5329102); Oenothein B (PubChem CID: 16132398); Tofacitinib (PubChem CID: 9926791); Fostamatinib (PubChem CID: 11671467); Vasoactive intestinal peptide (PubChem CID: 16129679); TGF-β (PubChem CID: 56842206); IL-10 (PubChem CID: 146070).
1. Introduction The immune system provides protection against infection and maintains immune homeostasis. Dendritic cells (DCs) play a central role in the induction of immunity as well as inducing intrathymic and peripheral tolerance. Clinical autoimmunity arises as a result of aberrant regulation of the immune responses [1]. The development of autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus(SLE), requires three different but related processes: disruption of immune tolerance, development of chronic inflammation in one or several organs, and tissue destruction and their harmful effects [2]. Classical treatment for autoimmune diseases is usually a combination of anti-inflammatory, immunosuppressive drugs and biological agents that are designed to block the activity of pro-inflammatory cytokines and lymphocytes as the primary cellular targets. However, the strategy is not so effective in controlling symptoms and disease progression. Accumulating evidence indicates that the central role of DCs in immunity and tolerance is an indispensable component in the pathogenesis of autoimmune diseases [3]. Therefore, targeting DC functions maybe a potential and valuable therapy for the control of autoimmune diseases. DCs
represent
a
heterogeneous
population
of
uniquely
well-equipped
antigen-presenting cells (APCs) with distinct developmental origins, phenotype markers and immunological functions. After generated from stem cells in the bone marrow, DCs are generally immature and traffic to the peripheral tissues, where they undergo several molecular events (namely antigen uptake, phenotypic and functional maturation, migration to the secondary lymphoid organs and present acquired antigens to naive T lymphocytes). Then, they instruct naive T cells to differentiate toward T helper (Th) -1(Th1), Th2, Th17 or regulatory T cell (Treg) cells as well as to promote maturation of antibody-producing B cells [4, 5]. These processes enable DCs to behave as critical sentinels to eliminate invading pathogens, to induce and regulate of most adaptive immune responses and to maintain tolerance and immune homeostasis [6-9]. Disregulation of these processes may cause imbalance of immune responses and lead to autoimmunity. Animal studies indicate that DCs play important
roles in the initiation and perpetuation of autoimmune diseases [10]. In this review, we present a description of key molecules and mechanisms that regulate DC differentiation, endocytosis, maturation and migration, especially focusing on their significances or potentials as pharmacological drugs or agents in anti-inflammation or immunosuppression for autoimmune diseases.
2. Molecular control of DC biology in autoimmunity 2.1 DC differentiation in autoimmunity After several decades of research, we have known that DCs stem from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as an unique hematopoietic branch [10, 11]. Accumulated evidence suggests different DC lineages play different roles in the maintenance of immune homeostasis via induction of immune tolerance and regulation. Under the mediation of some factors, DC precursors can be instructed to differentiate into immunogenic DCs and tolerogenic DCs. Immunogenic DCs have the ability of up-regulation the expression of co-stimulatory molecules (CD40, CD80 and CD86), MHC class II molecules and proinflammatory cytokines such as interleukin-12 (IL-12), tumor necrosis factor (TNF-α) and IL-6, and presenting antigens to specific T cells to elicit adaptive immune responses. Conversely, although tolerogenic DCs retain the ability of presenting antigens to specific T cells, they downregulate the expression of co-stimulatory molecules and proinflammatory cytokines, upregulate the expression of inhibitory molecules and anti-inflammatory cytokines and are resistant to maturation-inducing signals. The process is crucial for maintenance of immune homeostasis and control of autoimmune disorders. Hence, molecular control of DC differentiation maybe the pharmacological potential targets for the control of autoimmune diseases. Previous reviews have reported that pharmacological effects on DC differentiation and expansion can be achieved by immunomodulatory drugs, such as corticosteroids [12, 13], vitamin D3 [14-16], or corticosteroids plus vitamin D3 [13, 17-22], rapamycin [23-27], aspirin [28-30], N-acetyl-L-cysteine [31], mycophenolate mofetil [32, 33], butyric acid [34-36], rosiglitazone [37, 38], rabeximod [39] , n-3
fatty acid [40] and serial chinese herbal medicine [41]. These agents that have been widely used in the treatment of autoimmune diseases are previously reported to block DC differentiation quantitatively by antagonizing the effects of several key molecules, such as hematopoietic cytokines. Generally different hematopoietic molecules control the differentiation and expansion of bone-marrow(BM) cells toward DC specific lineage and maintain DC homeostasis in the periphery [10]. Here, we will present key hematopoietic cytokines that control DC differentiation and their significance in the treatment of autoimmune diseases.
FMS-like tyrosine kinase-3 Ligand (Flt3L) is a key mediators for DC generation [42]. Loss of Flt3 expression in hematopoietic progenitors correlates with the loss of DC differentiation potential [43, 44]. Treatment with Flt3L tyrosine kinase inhibitors or genetic deletion of Flt3L gene in mice leads to 10-fold decrease of pDCs and DCs in lymphoid organs [45], whereas enforcement of Flt3L expression in progenitors that lack the ability to develop into DC restores some DC developmental potential [46]. Prior studies showed that Flt3L was associated with autoimmune pathogenesis. In rheumatoid arthritis, Flt3L is increased in synovial fluid and correlated with active lesions [47]. In collagen-induced arthritis, Flt3L deficiency mice showed a marked increase in the scores and incidence of arthritis in both acute and chronic phases of CIA model mice as compared with wild type mice [48]. A Flt3-Flt3L pathway inhibitor sunitinib can reduce the intensity of synovitis and the incidence of bone destruction in bovine serum albumin (mBSA)-induced arthritis, which was achieved partly by the inhibition on DC differentiation [49]. Whereas increasing the number of DCs by Flt3L injection leads to an increase in the number of regulatory T cells, which contributes to the protection of mice from developing type 1diabetes(T1D) [50]. Due to the dual effects of Flt3L in both promoting and suppressing autoimmunity, the effects of Flt3L on DC precursors at their different developmental stages during the progress of autoimmune diseases need further investigation.
Granulocyte-macrophage colony stimulating factor(GM-CSF), a hematopoietic growth factor that regulates the differentiation of the myeloid lineage genitor cells, plays a critical role in the differentiation of mouse and human hematopoietic progenitors and monocytes into DCs. Accumulated evidence has shown that GM-CSF affects DCs on multiple levels during the pathogenesis of autoimmune diseases [51-54]. Under the influence of elevated GM-CSF, circulating inflammatory monocytes develops into inflammatory DCs that can present self-antigens to T cells and elicit autoimmune responses [55, 56]. Moreover, after antigen uptake and stimulation by the GM-CSF, DCs acquire enhanced life span and presentation ability to active T cells in the lymph nodes and cause autoimmunity [55]. Prior experiments in vitro showed that the GM-CSF stimulated monocyte-derived DC (moDC) maintained
their
inflammatory
property
and
increased
the
secretion
of
pro-inflammatory cytokines TNF-α and IL-6 [56, 57]. And GM-CSF could stimulate immature myeloid cells to differentiate into DCs in the central nervous system (CNS) and exacerbate experimental autoimmune encephalomyelitis (EAE) [58, 59]. Whereas apart from its key roles in the initiation and progression of DC-mediated autoimmunity, GM-CSF also suppresses the immune responses via its effect on DCs. Previous studies have reported that low-dose GM-CSF prevents the development of various autoimmune diseases in mice, through induction of tolerogenic CD8- myeloid DCs from bone marrow precursors and expansion of Foxp3+Tregs [60, 61]. Due to crucial role of GM-CSF in the differentiation and expansion of DCs, currently three anti-GM-CSF antibodies (CAM-3001, MOR103 and KB003) are tested for the pre-clinical treatment of diseases such as multiple sclerosis(MS), RA and asthma. The results showed rapid and significant beneficial effects on autoimmune diseases with no or less unexpected safety concerns [62-64].
Macrophage colony-stimulating factor (M-CSF), also named CSF-1, is a hematopoietic cytokine that mediates the proliferation and differentiation of macrophages [65]. And, M-CSF binds specifically to its receptor(CSF-1R) and partially regulates the differentiation or survival of nonlymphoid DCs [66, 67].
Epidermal langerhans cell (LCs) are totally absent in Csf-1R deficiency mice [68]. In the presence of M-CSF, circulating inflammatory monocytes develop into tolerogenic DCs that maintain the ability of antigen presentation, whereas downregulate expression of co-stimulatory molecules and proinflammatory cytokines [69]. In addition, injection of M-CSF increases both lymphoid organ pDCs and DCs in mice [70, 71]. Taken together, given their crucial roles in DC and autoimmunity, hematopoietic cytokines(e.g Flt3L, GM-CSF, M-CSF) can serve as potential targets to affect DC genesis as well as functions to prevent the development of autoimmune disease.
2.2 DC endocytosis in autoimmunity Haematopoietic stem cells differentiate into immature DCs that are recruited to peripheral tissues, where they continuously take up and process antigens by different endosomal
pathways
[11].
Previous
studies
have
reported
that
several
immunosuppressive mediators potently manipulate the function of DC endocytosis via distinct mechanisms. Some agents, like corticosteroids [12], vitamin D3 [14, 15] ,aspirin [34] and fumarates [72] inhibit phenotypic and functional DC maturation, and
consequently
enhance
endocytic
capacity.
Whereas
some
other
immunosuppressors suppress DC endocytosis by down-regulating the expression of DC endocytosis receptors in a DC-maturation-independent manner. The main agents are rapamycin, sanglifehrin, cyclosporine A (CsA) [34, 73, 74] and quercetin [75]. In the steady state, immature DCs selectively express plenty of endocytosis receptors, such as Fcγ receptors(FcγRs), mannose receptor(MRs), and heat shock protein receptors, which could be used to target antigens for processing and presentation in vivo [8].
Fcγ receptors(FcγRs), a family of endocytotic receptors for the Fc portion of immunoglobulin, confer the protective effects of the immune system by recognition of IgG bound pathogens and play a critical role in autoimmune diseases [76]. Both human and mouse immature DCs express several FcγRs, and the activating
FcγRs(FcγR and FcγRⅢ) enhanc DC activation via immunoreceptor tyrosine-based activation motif (ITAM) ,while the inhibitory FcR (FcγR ) regulates DC function to promote Treg induction but inhibit effector T cell responses via immunoreceptor tyrosine-based inhibitory motif (ITIM) [77, 78]. Prior studies suggest that activating FcγR(FcγR and FcγRⅢ) deficiency protects from autoimmune diseases, such as arthritis and lupus [79]. TG19320, a tetrameric peptide interfere with IgG/FcγR interaction, attenuates kidney damage and prolongs the survival rate of lupus-prone MRL/lpr mice [80]. Moreover, mouse anti-human FcγRⅢ mAb 3G8 has been used to successfully treat immune thrombocytopenia (ITP) [81, 82]. Conversely, inhibitory FcR(FcγR Ⅱ ) suppresses the expression of proinflammatory cytokines of DCs stimulated by toll-like receptor (TLR) 4 via lipid kinase phosphoinositied 3-OH kinase(PI3K)/AKT signaling pathway [83]. And FcγR Ⅱ -overexpressing DCs dramatically prevents glomerulonephritis and enhances the survival rate of lupus-prone MRL/lpr mice [84]. Additionally, FcγRⅡspecific small chemical entities suppress arthritis development in a collagen-induced arthritis(CIA) model, an suppressive effect even stronger than methotrexate(MTX), a classical drug for RA in human [85]. Currently, FcγRs are appealing targets in the treatment of inflammatory autoimmune diseases. Targeting approaches include blocking activating FcγR and activating inhibitory Fc γ RⅡ.
DEC205 is an endocytotic receptor and highly expressed on several subsets of DCs [86]. Accumulating evidence suggests that DEC205 plays an important role for the induction of immunity and tolerance [87]. Prior studies have suggested that selective delivery of antigens to DEC205 on steady-state DCs confers a powerful method to induce antigen-specific T cell tolerance [88]. And recombinant anti-DEC205 Abs fused to disease-relevant autoantigens have been developed and used successfully for tolerogenic protection from autoimmunity in mouse models of autoimmune diabetes, encephalomyelitis and arthritis [89-91].
Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is a typeⅡC-type lectin receptor that is abundantly expressed on DCs, especially immature DCs. Apart from being an adhesion molecule, DC-SIGN has emerged as a key player in the regulation of immune responses by recognition with several endogenous and exogenous antigens [92, 93]. As DC-specific phenotypic marker, DC-SIGN commonly recognizes intestinal commensal, which promotes DC induced generation of Tregs and prevents the development of T cell-dependent colitis [94]. Hence, DC-SIGN maybe a potential and valuable target on DC endocytosis in autoimmunity.
2.3 DC maturation in autoimmunity DCs are specialized sentinels responsible for coordinating innate and adaptive immunity. DC function is dependent upon their sensitivity to environmental inflammatory signs that promotes cellular maturation, phenotype alteration, activation and migration. We now appreciate that various molecules, signals, and mechanisms control the maturation of steady-state DC. Corruption of these steady-state operatives has diverse immunological consequences and pinpoints DCs as potent therapy targets of autoimmune diseases [95]. 2.3.1 Pattern recognition receptors Pattern-recognition receptors (PRRs) consist of Toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), and retinoic acid–inducible gene (RIG)-I-like receptors (RLRs) [95, 96]. Although best known as probes employed by DCs to sense pathogens and other environmental stimuli, many PRRs also transduce potent DC maturation signals and play a critical roles in autoimmunity.
Toll-Like Receptors(TLRs) are ligand-dependent detection modules that facilitate key aspects of innate and adaptive immunity. TLR signals within DCs are critical for induction of immune responses, with some exceptions given the nature of the
immunogens. Multiple lines of evidence indicate that activating TLR signals induce DC phenotypic and functional maturation and systemic autoimmunity [97]. Psoriasis in human patients is associated with upregulation of host molecules that enhance nucleic acid sensing by TLRs of plasmacytoid dendritic cells (pDCs) [98]. Duplication of the TLR7 gene causes DC expansion, maturation, and systemic autoimmunity. TLR9 over expression to the cell surface of hematopoietic stem cells (HSCs) results in CD11c+ DC expansion and activation, which induces the secretion of multiple pro-inflammatory cytokines (TNF-α, IL-1β) and fatal inflammation in irradiated mouse recipients. Anti-malarial drugs chloroquine and hydroxychloroquine that have been widely used in treatment of autoimmune diseases block DC activation through TLR7 and TLR9 [99, 100]. Myeloid differentiation factor 88(MyD88), the common TLR adaptor, mediates activation of peripheral myeloid dendritic cells and directs differentiation of T cells toward autoimmune Th17 cells [101]. MyD88 deficiency protects MRL.Faslpr mice from systemic lupus erythematosus (SLE), which is associated with down-regulation of expansion, activation, and cytokine secretion by DCs [102]. However, not all TLR signals induce DC maturation and autoimmune responses. Certain microbial products (e.g yeast zymosan, yersinia pestis, schistosomamansoni, bordetella pertussis) promote unexpected tolerogenic responses in DCs by binding TLR2, TLR4 or TLR6 [103]. The mechanisms that commensal sampling by DCs confers protection from autoimmune diseases and the intracellular signaling cascades that drive those tolerogenic DC functions require further investigation. Therefore, TLRs and their agonists maybe another potential targets for the treatment of autoimmune diseases.
C-Type Lectin Receptors (CLRs) are a variety family of transmembrane molecules containing the C-type lectin protein domain that enables binding of Ca2+ or carbohydrate ligands of commensal sampling. In most cases, CLRs down-regulate DC functions. For example, BDCA-2-Syk signals in human pDCs restrict interferon (IFN)-α
production
[104,
inhibition motif (ITIM)-containing
105]. CLRs
Immunoreceptor tyrosine-based that
activate
Src-homology
phosphatase(SHP) phosphatases can transduce negative maturation signaling in DCs. SHP-1 deficiency specifically up-regulates the expression of co-stimulatory molecules and MHC class
on DCs and leads to autoimmunity [106, 107]. Dendritic cell
immunoreceptor 1(DCIR1) is the only CLR whose genetic deletion in mice elicits spontaneous
autoimmune
disease
and
break
of
immune
homeostasis.
DCIR1-deficient mice develop IgM rheumatoid factor and antinuclear antibodies by 4-6 months of age, and arthritis develops in 30% of mice. In monocyte-derived DCs deprived from human, DCIR inhibits TLR-induced cytokine production [108, 109]. Those potential roles of CLR ligands in DCs may constitute an exciting prospect that may yield disease modulatory treatments with therapeutic value in autoimmune diseases.
Nucleotide oligomerization domain-like Receptors(NLRs) NLRs are cytoplasmic receptors that use their caspase recruitment domains to activate NF-κB or inflammasome to control the production of IL-1β and IL-18 [110, 111]. Nucleotide oligomerization domain (Nod) 2, which recognizes bacterial peptidoglycans, regulates some aspects of DC biology [112]. In graft versus host disease (GVHD), Nod2 knockout-DCs show enhanced phenotypic and functional maturation [113]. And Nod2 deficiency in mice displays gain-of-function and increased inflammatory cytokine secretion in DCs that causes increased susceptibility to DSS colitis [114]. These findings indicate a potential value for down-regulated DC Nod2 signals in the pathogenesis of autoimmune disease. Collectively, those potential mechanisms add intrigue to our understanding of the identity of PRRs. As the steady-state functions of those receptors may confer protection from autoimmune diseases, further pharmalogical development may constitute an exciting future with therapeutic value [115]. 2.3.2 Transcription factors Transcription factors, such as nuclear factor-kappa B (NF-κB), class O of forkhead box transcription factor(Foxo)3 and T-bet, potently manipulate DC phenotypic and functional maturation via upstream activating signals, and also play
critical role in autoimmunity. NF-κB is a signal transduction pathway molecule crucially involved in the inflammatory responses. Previous study reported that a common feature of drugs targeting DCs was their capacity to inhibit NF-κB, such as corticosteroids [12], CsA [73, 74], vitamin D3 analogs [35]. The NF-κB family member RelB is required for myeloid DC differentiation, and controls DC function via regulation of CD40 and MHC class II molecule expression [35]. Whereas another NF-κB family member NF-κB1, crucial for maintaining the resting state of DCs, restricts DC production of TNF-α [116, 117]. NF-κB inhibitor Bay11-7082 suppresses both CD40 and MHCⅡ expression and cytokine production on NiSO4 stimulated DCs [118, 119]. Bay11-7082 treated DCs prevent the development of collagen-induce arthritis (CIA) and inhibit CII specific T lymphocyte proliferation and antibody production [120]. Currently, a phase I clinical trial with tolerogenic DCs generated with Bay11-7082 is carried out in patients with RA. It has been found that DCs modified by Bay11-7082 were well tolerated and no major adverse effects were observed in this trial [121]. FOXO3, a member of Foxo family, was previously reported to play critical roles in
DC
function
through
a
“reverse
signaling”
process
mediated
cytotoxic T lymphocyte-associated antigen-4
(CTLA-4)
interaction
with
by B7
molecules resulting in increased indoleamine 2,3-dioxygenase (IDO) levels [95]. And siRNA-silenced Foxo3 expression leads to a decrease of DC tolerogenicity and expression of suppressive factors transforming growth factor (TGF)-β, and a concomitant increase in expression of CD80 and IL-6 [122]. And Foxo3 deficiency in steady state leads to 2-fold cellular expansion of splenic DCs and modest up-regulation of CD80 and CD86 in DCs [123]. Also Foxo3 restricts DC production of IL-6 and to a lesser extent of TNF-α and CCL2 [124]. In autoimmunity, prior study reported that Foxo3 activity was a predictive indicator of disease severity in Crohn's disease (CD) and rheumatoid arthritis [125]. And genetic manipulation in Foxo3 led to milder CD and lesser inflammatory responses, and was also associated with a milder course of RA but with increased susceptibility to more severe malaria [126]. In summary, those data suggest that Foxo3 may be part of the regulatory mechanisms
that program DC maturation and immune responses and can be a useful target in immune based therapies. T-bet is a transcription factor mostly noted for its role in T effector cell differentiation, but its role in DCs seems negative. The effect of T-bet on DC immunobiology depends mainly on the relationship between T-bet-mediated suppression of DC-produced TNF-α and TNF-α-dependent progression of colitis. T-bet-deficiency in DCs confers TNF-α over-express and triggers spontaneous ulcerative colitis with progressive development to colorectal cancer. And patients suffering inflammatory bowel disease are often successfully treated with anti-TNF-α therapy [127-129]. 2.3.3 Immune mediators DC maturation encompasses the down regulation of endocytic capacity, the up-regulation of surface T-cell co-stimulatory (CD40, CD80 and CD86) and MHC class II molecules, the production of bioactive pro-inflammatory cyokines such as IL-12, TNF-α and IL-6 and the inhibition of anti-inflammatory cyokines such as IL-10 and TGF-β. These immune mediators control steady-state DC maturation and disruption of these factors leads to diverse immunological consequences and pinpoints DCs as potent drivers of autoimmune disease. Thus, targeting on these immune mediators may result in therapeutic values in autoimmune diseases. Most anti-inflammatory and immunosuppressive mediators suppressed immune responses are coupled with inhibition in DC phenotypic and functional maturation. These mediators include immunosuppressive drugs such as corticosteroids [12, 13], vitamin D3 [14-17], rapamycin [23-27], CsA [73, 74], tacrolimus [130], aspirin [28-30], mycophenolate [32, 33], sanglifehrin A [131], leflunomide [132], intravenous immunoglobulin(IVIG) [133] rosiglitazone [37, 38] and troglitazone [18]; the mucolytic antioxidant N-acetyl-L-cysteine [31]; anti-malarial drugs such as chloroquine and hydroxychloroquine [134, 135]; pro-inflammatory factor blockers such as TNF-α blocker (adalimumab [136], infliximab [137]), and IL-6 blocker(tocilizumab [138]); anti-inflammatory factors such as IL-10 [139-144],TGF-β [145-148]; vascular endothelial growth factor (VEGF), PGE2, retinoids, HLAG,
flavonoid [9, 35, 103, 149-151], and several Chinese herbal medicine and their components [41, 72, 132] [152](for detail seen Tab.1) Co-stimulatory and MHC class II molecules
DCs have a dual ability to either
activate or suppress immunity, which is mainly associated with the expression of co-stimulatory and MHC class II molecules [153]. In addition to chemical or tissue culture induced tolerogenic DCs, genetic engineering methods can also be used for the creation of tolerogenic DCs. Recent studies indicate that gene silencing of CD40, CD80,and CD86 through administering short interfering RNA (siRNA) achieves optimal protection from disease and induced antigen-specific Tregs in CIA mice [154, 155]. Apart from co-stimulatory molecules, MHC class II molecules are indispensable for DC immune biology. In the steady state, MHC class II molecules connect with a single lysine by ubiquitin chains. And once DC activated, deubiquitination will happen in MHC class II molecules, which leads to accumulation of MHC class II on DC cell surface [155-158]. Thus, blocking the deubiquitination and maintaining ubiquitination of MHC class II will be a potential target on preventing immune responses in autoimmune diseases. The ubiquitin-conjugating molecule MARCH1 is primarily expressed in immature DCs, and has the effect to down regulate DC activation. MARCH1-deficient DCs express 10- fold higher levels of MHC class II molecules and CD86, but with significantly reduced cytokine responses to LPS and CD40 ligand and diminished capacity to present MHC class II restricted antigens [156, 159]. The mechanisms and significances of the contradictory effects of MARCH1-deficient DCs require further investigated. Collectively, those data offer a new insight in targeting DC phenotypic maturation to manipulate the treatment of autoimmunity. Cyokines. Once activated, DCs undergo functional maturation and produce multiple cytokines, including pro-inflammatory cytokines such as TNF-α, IL-6, IL-12 and IL-1β, and anti -inflammatory cytokines such as IL-10, TGF-β [1, 160]. Those cytokines play critical roles in autoimmune responses. As the products of DCs, they also induce the differentiation of immature DCs into mature DCs that can instruct naive T cells differentiating toward Th1, Th2, Th17 or Treg cells [160]. Due to their
potential on regulating the balance between immunity and tolerance, the bioavailability of those cytokines and their effect on DC functions have been implicated in inflammatory and autoimmune diseases. Currently, biological agents targeting on cytokines TNF-α, IL-6 and IL-1 are widely used in autoimmune diseases, such as RA, Crohn’s disease, psoriatic arthritis (PsA), and ankylosing spondylitis(AS) [161-167]. This represents a success of immunology in clinical application and the coming years will witness the expanding benefit of cytokines as therapeutic targets in autoinflammatory and autoimmune pathology. Apart from pro-inflammatory cytokines, anti-inflammatory cytokines IL-10, TGF-β directly targeting on DC functions, are powerful tolerogenic agents which induce tolerogenic DCs to secrete even higher levels of anti-inflammatory cytokines. IL-10 interferes with differentiation of peripheral blood monocytes to DCs and induces cells with a tolerogenic phenotype [168]. Addition of IL-10 to differentiation cocktail induces a sustained inhibitory effect on subsequent maturation of monocyte-derived DCs And exogenous IL-10 reduced the expression of MHCⅡand CD80, decreased IL-12p40 level, and increased IL-10 level in DC, which resulted in impaired capacity to stimulate allogenic T-cell proliferation [169]. IT9302, a nonameric peptide homologous to the C-terminal domain of human IL-10, can promote monocyte differentiation to tolerogenic DCs through mechanisms involving STAT3 inactivation and NF-κB intracellular pathway blockade [170]. And IL-10 induced tolerogenic DCs were previously reported to prolong allograft survival by blocking the expression of CD80 and CD86, leading to apoptosis of allospecific T cells [171]. Similar to IL-10, TGF-β utilizes distinct pathways to reduce the expression of CD80 and CD86 by DCs and suppresses IL-12 production, giving rise to a reduced capacity to prime T cells [172]. Moreover, tolerogenic DCs stimulated by TGF-β delayed corneal allograft rejection by up-regulation the number of Foxp3+ Tregs [173]. And treatment of grafted β-cells islets with TGF-β-generated tolerogenic DCs prolonged graft survival [174]. Besides, genetic manipulation of DC maturation has allowed DC up-regulation of IL-10 and TGF-β that inhibit antigen presenting process. And those genetically programmed DCs display tolerogenic function through various mechanisms and some
of them even show therapeutic potential for graft rejection and autoimmune diseases [103]. 2.3.4 Other regulators Several other molecules have been found to intrinsically regulate DC maturation, and importantly, absence of any one of these regulators results in evident development of autoimmune diseases in mouse models. These intrinsic controllers have different protein characters, including αvβ8 integrin [175]; signal transducer and activator of transcription 3 (STAT3) [176] and A20 [95]. αvβ8 integrin expressed by DCs activates latent TGF-β and is critical for immune homeostasis [177]. Mice with DCs lacking αvβ8 and those lacking αvβ8 on all immune cells displayed similar pathologies of splenomegaly, lymphadenopathy, spontaneous T cell activation, autoantibodies, and colitis [175]. STAT3-mediated transcription was required to suppress activation markers on DCs [178]. Moreover, DCs can be categorized by the levels of cellular STAT3 phosphorylation/activation [178], the highest of which correlates with low expression of MHC class II. Thus, those molecules serve as ‘domestic police’ that inhibit DC dysfunction and the subsequent T cell disorder, and eventually contribute to the prevention of autoimmune diseases. A20, the product of the TNFAIP3 gene, restricts a number of innate immune signaling cascades that regulate DC functions, including TLR, NOD2, CD40, and TNF signals [179-181].
2.4 DC migration in autoimmunity The ability of DCs to initiate and orchestrate adaptive immune responses is a consequence of their localization within tissues and their specialized capacity for migration. Accumulating evidence indicates that trafficking molecule matrix metalloproteinases (MMPs) [182, 183], chemokines and their receptors [184] and adhesion molecules [185] play critical roles in orchestrating DC migration. Once a mobilization signal has triggered detachment from parenchymal tissues, maturing DC secrete MMPs to disintegrate extracellular matrix (ECM) barriers. Then under the regulation of chemokines and adhesion molecules, DCs traffic to secondary lymphoid organs to present the antigen to T cells and elicit the adaptive immune responses, and
consequently result in autoimmune diseases. Hence, pharmacological inhibition on DC migration will contribute to the prevention of autoimmune diseases. Prior studies have reported that pharmacological effects on DC migration can be achieved by immunomodulatory agents, including immunosuppressant such as corticosteroids [34, 186], vitamin D3 [34], CsA [34, 73, 74], mycophenolate [187] and leflunomide [188, 189]; Chinese herbal medicine such as triptolide [190], apigenin [191] and quercetin [75]; cytokines such as IL-10 [192], IL-21 [193], M-CSF [194]. These agents modulate DC migration primarily via control of trafficking molecules. Here, we review the key molecular traffic signals that govern the migration of DCs and provide novel insights into the significance of DC migration in the treatment of autoimmune diseases.
2.4.1 Matrix metalloproteinases Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9 serve to disintegrate extracellular matrix(ECM) barriers, such as collagen types I-IV, fibronectin, and laminin [182, 195], which enables DCs to traffick through interstitial space to afferent lymph vessels. MMPs have been found to be key molecules in DC migration. Neutralizing or suppressing antibodies to MMP activity inhibits DC migration in Matrigel assays as well as langerhans cell(LC) emigration from skin explants [196, 197]. And MMP-9-deficient DCs in vitro are markedly defective in transepithelial migration and move poorly to LNs in vivo [198]. Inhibitors of metalloproteinases (TIMPs) and endogenous regulators of MMP activity have been suggested to block interstitial DC migration [182]. Furthermore, previous study showed that over-expression of genes encoding MMPs, such as MMP-1, -10 and -12 correlated with enhanced migratory capacity of DCs measured in Matrigel assays [199]. Besides, studies have suggested that MMPs(especially MMP-9) play a critical role in autoimmune disease. Over production of MMP-9 have been found in the sera and synovial fluid (SF) from patients with RA [200]. And the increased level of MMP-9 activity in the synovial fluid of RA and the severity of the disease has been correlated [201]. MMP-9 deficient mice showed inhibition of the development of
antibody-induced arthritis, one of the murine models of RA. The mechanisms that MMP-9 promote arthritis development may result from the effect of MMP-9 on migration of inflammatory cells, such as DCs [202]. Those findings indicate a potential role of MMPs in DC migration in the pathogenesis of autoimmune diseases and pharmacological inhibition on MMPs may constitute an exciting future for the treatment of autoimmune diseases. 2.4.2 Chemokines and the receptors Chemokines are small-secreted chemotactic cytokines that regulate the migration of leukocytes under steady state and inflammatory conditions. The migratory pathway of DCs start with recognition of a mobilizing signal induced by a variety of maturation factors, such as IL-1β, TNF-α and LPS [203]. Administration of these molecules leads to the loss of DCs from the periphery within a few hours. Pharmacological inhibitors or neutralizing antibodies of IL-1β or TNF-α impair mobilization and migration of DCs [203, 204]. Corticosteroids inhibit DC migration to lymphoid tissues through suppressing the inflammatory cytokine production. DC activation initiates a significant change in the repertoire of chemokine receptors (CCRs) [186]. The dominant chemokine pathway for DC migration to lymph nodes via lymphatics is CCR7 and its ligands, CCL19 and CCL21. CCR7-deficient mice show defective DC migration to LNs, which results in fewer putative migratory DCs in LNs after contact sensitization [205, 206]. Mobilizing signal induced by TNF-α significantly up-regulates the expression of CCL21 secreted by lymphatic endothelial cells, thus making the reactive vessels even more attractive to migrating DCs [207, 208]. Neutralizing antibodies to CCL21 has been suggested to inhibit the migration of skin-derived DCs into skin-draining LNs [209]. The cyclophilin-binding agent sanglifehrin A can suppress DC migration by suppressing CCL5, CCL17, CCL19, CXCL9 and CXCL10 expression in human monocyte-derived DCs [210]. IFN-β inhibits DC migration through STAT-1–mediated transcriptional suppression of CCR7 [211]. Chinese herbal derived immunosuppressive medicine triptolide impairs DC migration by inhibiting CCR7 and COX-2 expression [190] . Some flavonoid compounds like quercetin and apigenin can also inhibit DC migration through
down-regulation of chemokines and their receptors [75, 191]. Several other chemokine receptors play a role in DC traffic from the periphery to draining lymph nodes but appear less important. Migration of plasmacytoid DCs (pDCs ) activated with CpG for 24 h from peripheral blood into the lymph nodes has been indicated to depend on the CXCR3 and ligand CXCL9 [212]. CXCR4 inhibition impairs migration of LCs and dermal DCs to draining LNs [213]. Moreover, emigration of skin-DCs and lung-DCs [214] to the draining lymph node was partially blocked in CCR8-deficient mice. Hence, chemokine receptors are essential in lymph node homing of endogenous DCs. And pharmacological therapy on DC migration may target on down-regulation the expression of chemokine receptors on DCs or local chemokine expression. 2.4.3 Adhesion molecules In addition to acquiring the capacity to across ECM barriers, maturing DCs must develop the ability to entry into lymphatic system. Accumulating evidence indicates that multiple traffic molecules play a role in DC migration through the lymphatic system [4]. The best-validated molecules for DC migration into afferent lymphatics are adhesion molecules. After pro-inflammation-cytokine stimulation, lymphatic endothelial cells up regulate adhesion molecules and form tight and adherens junctions, resulting in DC trafficking within the afferent lymphatics [215, 216]. The key adhesion molecules for DC migration included selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and their respective receptors [216]. Related study showed that antibody neutralization or suppression on VCAM-1 and ICAM-1expression can block DC adhesion to lymphatic endothelium and migration into afferent lymph vessels both in vitro and in vivo [217, 218]. And ICAM-1 deficiency mice also showed impaired langerhans cell migration to lymph nodes(LNs) [219]. P-selectin glycoprotein ligand-1 (PSGL-1) is the ligand for P-selectin and highly expressed on DCs. Prior study suggests that antibody against PSGL-1 block DC migration into LNs [220]. Similarly, integrin α6 is upregulated and contributes to migration of LCs [221]. Currently, the inhibition of adhesion molecules has been found to prevent or ameliorate disease severity in animal
models and clinical studies [216, 222]. Treatment with anti-ICAM-1 monoclonal antibody(mAb) have been found to reduce the severity of collagen- induced arthritis in mice and adjuvant induced arthritis in rats and to prolong the survival of cardiac allografts in mice [222-224]. Whereas pre-clinical studies of an antisense oligonucleotide to human ICAM-1 in Crohn’s disease and RA demonstrated no significant differences in disease severity between the placebo and treated patients [216, 225]. Similarly, related studies showed that anti-E-selectin mAb treatment protected against adjuvant-induced arthritis and colitis in animal models [216, 226], but not effective in the treatment of psoriasis in a randomized clinical trial [227]. However, not all the adhesion blockade studies show disappointing results. The anti-CD11a (the receptor of ICAM-1) mAb, efalizumab, has shown promising results in psoriasis patients. And the anti-α4 mAb, natalizumab, has proven to be safe and efficacious in patients with multiple sclerosis [228] or Crohn’s disease [229]. Taken together, adhesive interaction is a most important aspect of DC migration and understanding the underlying mechanisms may provide new potential therapeutic targets to modulate immune responses in autoimmune diseases. 2.4.4 S1P and receptors Sphingosine-1-phosphate (S1P), a potent bioactive sphingolipid metabolite that regulates many cellular processes including cell survival, cytoskeletal rearrangements, cell migration, and production of cytokines and chemokines , is involved in many kinds of diseases such as atherosclerosis, cancer, asthma and autoimmune diseases [230, 231]. S1P and its receptors also play a role in the interstitial migration of fully differentiated DCs. The novel immune-modulator FTY720 is a chemical derivative of myriocin, and its phosphorylated metabolite FTY720-P is a structural homolog of S1P. FTY720 inhibits S1P function through internalizing of S1P receptors, making cells unresponsive to S1P [232]. Researchers have demonstrated FTY720 could alleviate the clinical signs of experimental asthma, allergic contact dermatitis, and skin allograft transplantation through impairing DC trafficking to draining LNs [233-235]. Our recent study showed that FTY720 treatment also significantly suppressed the incidence and severity of collagen-induced arthritis (CIA) in DBA/1J mice via the
modulation of DC migration. CCR7 down-regulation on DCs and decreased CCL19 secretion are responsible for the impairment of DC migration by FTY720. The results indicate inhibition on migration by FTY720 may provide a novel approach in treating autoimmune disease such as RA[236]. And FTY720 has been shown to be a useful agent for the prevention of transplant rejection and has been proved by FDA to treat MS [237]. 2.4.5 Others molecules Factors present in inflammatory sites, such as lipid mediators, particularly prostaglandin E2 (PGE2) [238], and the high mobility group box-1 (HMGB1) protein [239], have been shown to induce migration of maturing DCs. The role of PGE2 in DC migration is strongly supported by the fact that mice deficient in the PGE2 receptor EP4 or wild-type mice treated with an EP4 antagonist exhibit reduced DC migration to lymph nodes [240]. The PGE2-induced DC migration is mediated through up-regulates MMP-9 expression, including both secreted and membranebound MMP-9 [183]. Besides, Faure-Andre and colleagues recently noted that DC migration was regulated by Ii, a key intracellular chaperone of MHC class II molecules that directs MHC class II endosomal localization and enables peptide loading. Ii-mediated association and activation of myosin light chain, which mediates cell migration, may enable DCs to effectively probe the tissue microenvironment [241]. DCs express cannabinoid receptor 2 (CBR2) and CBR2 agonists decrease autoimmune inflammation and DC production of pro-inflamamtory cytokines and capacity to stimulate CD4+ T cells. CBR2 agonists were found to inhibit DC migration from peripheral tissues by blocking MMP9 expression [242] .
3. Conclusion As the most powerful APC, DCs serve as the key bridge between innate and adaptive immunity. DCs also function as a critical switcher between immune activation and immune tolerance. To be a truly effective immune system manipulator, DCs must endure many steps of evolution. And each step was regulated subtly by a
variety of molecules. These steps, from differentiation, endocytosis to maturation and migration, are closely associated with the function of DCs and the outcome of immune response. Impaired endocytosis of dead cells by DCs is implicated in the pathogenesis of SLE; Different DC maturation state determines the immune system to be activated or tolerant; Migration is the prerequisite step for DCs to intact with T cells/B cells in LNs and orchestrate them subsequently. The complexity of DC evolution process and the flexibility of their property determine the biological basis of their variety functions and the ability to react with different environments efficiently. And also provide us with plenty therapeutic targets to manipulate them. Further studies in the mechanisms of current drugs or novel molecules in DC functions will be of great significance for developing unpreceding protocols for the treatment of autoimmune diseases.
Conflict of interest The authors have no conflict of interest. Acknowledgments We thank the many researchers who have contributed to our current understanding of DC functions. This work was supported by grants from National Natural Science Foundation of China (Grant No.81202359，81471613)
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Figure legend Fig. 1. Targeting dendritic cell (DC) functions for treatment of autoimmune diseases. After generated from haematopoietic stem cell in the bone marrow, DCs are generally immature and traffic to the peripheral tissues, where they undergo several molecular events, namely differentiation, endocytosis, phenotypic and functional maturation, migration to the secondary lymphoid organs and present acquired antigens to naive T lymphocytes. And each event was regulated subtly by various molecules, signals, and mechanisms. HSC, haematopoietic stem cell; iDCs, immature dendritic cells; mDCs mature dendritic cells; LNs, Lymph nodes; ECM, extracellular matrixc, ECM.
Table 1. Representative immunomodulatory targets and their effects on DC functions. Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
[12, 22]
Study Differentiation
Dexamethasone
human
moDCs
in vitro
low levels of CD1a
Phenotypic
Cytokine
Migration
T Cell
maturation
production
MHC-II↓
TNF-α↓
CCL3↓
Less Th1/Th2
Immune-mediated diseases
stimulation
And other
CD40↓
IL-12↓
CCL2↓
cell generation,
Corticosteroids
CD86↓
IL-1β↓
CCL5↓
More Treg cell
CCL28↓
generation
CD54↓
CCL22↓ Vitamin D3
mouse
human
Dexamethasone +
mouse
BMDCs
moDCs
BMDCs
in vivo
in vitro
in vitro
(-)
low levels of CD1a
(-)
Vitamin D3
MHC-II↓
TNF-α↓
CCL3↑
More Treg cell
EAE,
CD80↓
IL-10↑
CCL2↑
generation
Autoimmunity
MHC-II↓
IL-10↑
CCL5↓
Less Th1/Th2
MS,
CD40↓
IL-12↓
CCL18↑
cell generation,
Autoimmunity
CD83↓
TNF-α↓
CCL22↓
More Treg cell
CD86↓
IL-6↓
[13, 14]
[15]
generation
MHC-II↓
IL-12↓
ICAM-1↓
Inhibit
CD40↓
INF-γ↓
CCL3↑
stimulation,
diseases
CD80↓
CCL2↑
CD86↓
CCL5↓
T-cell
Immune-mediated
[19,22]
CCR1,2,5,7↓ human
moDCs
in vitro pre-clinical
(-)
MHC-II↓
IL-10↑
Inhibit T-cell
graft rejection;
CD40↓
IL-12↓
stimulation,
Rheumatoid
CD83↓
TNF-α↓
arthitis; Sjogren
CD86↓
IL-6↓
syndrome
[16-21]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
[21]
Study Differentiation
Phenotypic
Cytokine
maturation
production
Migration
T Cell stimulation
MHC-II↓
IL-10↑
Less Th1
Rheumatoid
Dexamethasone
CD40↓
IL-12↓
cell generation,
arthritis;
+monophosphoryl
CD80↓
TNF-α↓
More Treg cell
Immune-mediated
lipid A
CD83↓
IL-23↓
generation
diseases;
human
moDCs
in vitro
(-)
CCL19↓,
Prevention of graft
CD86↓
rejection Rapamycin
mouse
BMDCs
in vitro
GM-CSF↓,
MHC-II↓
IL-12↓
IL-4R↓,
CD40↓
TNF-α↓
FLT3L↓
CD80↓
(-)
More Treg cell
Prevention of graft
generation
rejection
Reduce survival
Prevention of graft
of alloantigen
rejection
[23-25]
CD86↓ mouse
BMDCs
in vivo
(-)
(-)
(-)
(-)
[26]
specific CD8+ T cells human
moDCs
in vitro
(-)
CD40↓
(-)
(-)
CD80↓
More Treg cell
Immune-mediated
generation
diseases
[27]
CD86↓ Sanglifehrin A
human
moDCs
in vitro
(-)
(-)
IL-12↓ IL-23↓
(-)
(-)
Immune-mediated diseases
[131]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Inhibit T-cell
Immune-mediated
[74]
TNF-α↓
stimulation
diseases
IL-12↓
Lower Th1
Immune-mediated
TNF-α↓
cell generation,
diseases
Study Differentiation
Cyclosporin A
mouse
human
BMDCs
moDCs
in vitro
in vitro
(-)
(-)
Phenotypic
Cytokine
maturation
production
(-)
IL-12↓
(-)
Migration
T Cell stimulation
CCR7↓
[73]
More Treg cell generation Mycophenolate
mouse
BMDCs
in vitro
(-)
CD40↓
IL-12↓
ICAM-1↓
CD80↓
Inhibit T-cell
Immune-mediated
stimulation
diseases
[32]
CD86↓ human
Tacrolimus
mouse
moDCs
BMDCs
in vitro
in vivo
(-)
(-)
CD54↓
IL-10↓
Inhibit T-cell
Immune-mediated
CD80↓
IL-12↓
stimulation
diseases
CD83↓
TNF-α↓
CD86↓
IL-18↓
(-)
(-)
More Treg cell
CIA
[130]
More Treg cell
Rheumatoid
[130]
generation
arthritis
More Treg cell
CIA
generation
MS
(-)
(FK-506)
[33]
generation human
moDCs
in vitro
(-)
MHC-II↓
TNF-α↓
CD40↓
IL-10↑
(-)
CD80↓ CD86↓ FTY720
mouse
BMDCs
in vivo
(-)
(-)
IL-12↓
CCR7↓
[236, 237]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Inhibit T-cell
Immune-mediated
[134, 135]
stimulation
diseases
(-)
Immune-mediated
Study Differentiation
chloroquine
mouse
BMDCs
in vitro
(-)
Phenotypic
Cytokine
maturation
production
CD80↓
IL-10↓
CD86↓
IL-12↓
Migration
T Cell stimulation
(-)
TNF-α↓ Aspirin
human
moDCs
in vitro
(-)
CD83↓
IL-10↓
(-)
IL-12↓
[30]
diseases
TNF-α↑ mouse
Butyric acid
human
BMDCs
moDCs
in vitro
in vitro
promoted the
MHC-II↓
generation of CD11c+
CD40↓
DC;Phagocytosis
CD80↓
inhibition;
CD86↓
Differentiation
MHC-II↓
Inhibition;
CD40↓
reducing the phagocytic
CD86↓
capacity
CD83↓
IL-12↓
(-)
(-)
(-)
Inhibit T-cell
Immune-mediated
stimulation
diseases
Inhibit T-cell
Immune-mediated
stimulation
diseases
Inhibit T-cell
Immune-mediated
stimulation
diseases
Reduce T cell
Type-1 Diabetes
[28, 29]
[36]
CD86↓ N-acetyl-L-cystei
human
moDCs
in vitro
ne
(-)
MHC-II↓
IL-12↓
CD40↓
IL-6↓
CD86↓
IL-8↓
(-)
[31]
TNF-α↓ Troglitazone
human
moDCs
in vitro
(-)
priming
[17]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
Autoimmunity;
[37]
priming
EAE Type-1 Diabetes
[38]
Immune-mediated
[132]
Study Differentiation
Rosiglitazone
mouse
BMDCs
in vitro
(-)
Phenotypic
Cytokine
maturation
production
(-)
(-)
Migration
T Cell stimulation
(-)
human
moDCs
in vitro
CD1a↓
CD80↓
(-)
(-)
Reduce T cell
human
moDCs
in vitro
(-)
CD80↓
(-)
CCR7↓
(-)
priming leflunomide
CD86↓ Triptolide
Apigenin
human
mouse
mouse
moDCs
BMDCs
BMDCs
in vitro
in vitro
In vivo
CD1a↓
(-)
(-)
diseases
MHC-II↓
IL-12↓
CCR7↓,
Reduce T cell
Immune-mediated
CD40↓
TNF-α↓
CCR5↑,
priming;
diseases
CD80↓
IL-10↓
COX-2↓,
More Treg cell
CD86↓
TGF-β↓
MHC-II↓
IL-12↓
CD40↓,
TNF-α↓
CD80↓,
IL-10↓
CD86↓,
IL-1β↓
MHC-II↓
TNF-α↓
CD40↓
IL-6↓
CD80↓
IL-1β↓
[190]
generation CXCR4↓
(-)
(-)
[191]
CXCR4↓
(-)
CIA
[191]
[75]
CD86↓ Quercetin
mouse
BMDCs
in vitro
reducing the phagocytic
MHC-II↓
IL-12↓
CCL3↓
Reduce T cell
Immune-mediated
capacity
CD40↓
TNF-α↓
CCL2↓
priming
diseases
CD80↓
IL-10↓
CCL5↓
CD86↓
IL-1β↓
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
EAE
[151]
EAE
[72]
[242]
Study Differentiation
Chrysin
human
moDCs
In vivo
(-)
Phenotypic
Cytokine
maturation
production
MHC-II↓
IFN-γ↓
CD83↓
IL-12↓
Migration
T Cell stimulation
(-)
Less Th1 cell generation,
CD86↓
More Treg cell generation
Fumarates
mouse
BMDCs
in vitro
(-)
(-)
IL-12↓
More Treg cell
More Treg cell
IL-23↓
generation
generation
(-)
Reduce T cell
Immune-mediated
priming;
diseases
Reduce T cell
rheumatoid
priming;
arthritis;
IL-10↑ Auranofin
mouse
BMDCs
in vitro
inhibition of the
MHC-I↓
phagocytic activity of
MHC-II↓
(-)
DCs Rabeximod
human
moDCs
in vitro
CD1a↓,
MHC-I↓
IL-6↓
(-)
MHC-II↓
n-3 fatty acid
human
moDCs
in vitro
CD1a↓,
CD80↓
Immune-mediated
CD40↓
diseases
(-)
IL-6↓
(-)
(-)
Immune-mediated
[39]
[40]
diseases Glatiramer acetate
mouse
BMDCs
In vivo
(-)
(-)
IL-10↑
CCL2↓ CCL3↓ CCL5↓ IP-10↓
(-)
EAE
[152]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
Immune-mediated
[133]
priming;
diseases,
Study Differentiation
IVIg
human
moDCs
in vitro
CD1a↓
Phenotypic
Cytokine
maturation
production
MHC-II↓
TNF-α↓
CD83↓
IL-12↓
CD86↓
IL-10↑
Migration
T Cell stimulation
(-)
transplantation
CD40↓ Bay 11-7082
human
(NF-κB inhibitor)
human
in vitro
(-)
umbilical
CD83↓
IL-8↓
(-)
(-)
CD86↓
Immune-mediated
[121]
diseases
cord blood-DCs mouse
BMDCs
In vivo
(-)
(-)
(-)
(-)
Reduce T cell
CIA
[118-120]
Reduce T cell
SKG mice from
[243]
priming;
getting arthritis
response MHC-II↓
IL-6↓
(histone
CD40↓
IL-12↓
deacetylase
CD80↓
Trichostatin A
mouse
BMDCs
in vitro
(-)
mouse
BMDCs
In vivo
(Flt3 inhibitor) Oenothein B
Lupus
CD86↓
inhibitor) Sunitinib
(-)
Reduce CD11c+
(-)
(-)
(-)
(-)
population mouse
BMDCs
in vitro
CD1a↓,
antigen-induced
[49]
arthritis CD83↓
IL-6↓ IL-1β↓
(-)
(-)
inflammatory bowel disease, celiac disease, rheumatoid arthritis.
[244]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
rheumatoid
[137]
priming;
arthritis
Reduce T cell
rheumatoid
priming;
arthritis
Study Differentiation
Infliximab
human
moDCs
In vivo
(TNF-α blocker)
Less CD11c+ DCs
Phenotypic
Cytokine
maturation
production
(-)
Migration
T Cell stimulation
(-)
CD123+ DCs percentages
Tocilizumab
human
(-)
In vivo
(IL-6 blocker) Tofacitinib
reduction of circulating
(-)
IL-6↓,\
(-)
myeloid DCs human
moDCs
in vitro
(-)
CD80↓ CD86↓
IL-1β↓
mouse
BMDCs
in vitro
(-)
(-)
IFN-α↓
Chemokines
Reduce T cell
Immune-mediated
(spleen tyrosine
IL-2↓
IP-10↓
co-stimulator
diseases
kinase inhibitor)
IL-5↓
CCL3↓
(ICOS) and
( JAK inhibitor) Fostamatinib
IL-6↓
rheumatoid
[138] [245]
arthritis [246]
PD-1
IL-6↓ IL-13↓ IL-17↓ Vasoactive
mouse
BMDCs
in vitro;
endocytosis↑,
intestinal peptide
MHCⅡ↓
TNF-α↓
More Treg cell
Immune-mediated
CD40↓
IL-12↓
Generation, and
diseases
CD80↓
IL-6↓
Reduce T cell
CD86↓
IL-10↑
priming
(-)
[247]
CD83↓ TGF-β
mouse
BMDCs
In vivo
(-)
MHCⅡ↓
TNF-α↓
CD40↓
IL-12↓
CD80↓
IL-6↓
CD86↓
IL-1β↓
(-)
Reduce T cell
Type 1 Diabetes;
priming
Prevention of graft rejection
[146, 147]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
Systemic Lupus
[139-144]
priming;
Erythematosus;
Study Differentiation
IL-10
human
moDCs
Phenotypic
Cytokine
maturation
production
in vitro
CD1a↓,
MHC-Ⅱ↓
IL-12↓
pre-clinical
DC-SIGN↑,
MHC- ↓
IL-6↓
CD83↓
TNF-α↓
Migration
T Cell stimulation
CCR7↓
Type 1 Diabetes;
CD80↓
Immune-mediated
CD86↓
diseases; Asthma and allergy
rat
BMDCs
in vivo
(-)
CD86↓
(-)
(-)
Reduce T cell
Prevention of graft
priming and
rejection
[171]
allospecific T cell response mouse
BMDCs
(-)
MHCⅡ↓
IL-6↓
MHCⅠ↓
IL-12↓
B7-1↓
IL-23↓
(-)
Reduce T cell
delayed-type
priming
hypersensitivity
Reduce T cell
Anti-phospholipid
priming
syndrome;
[168]
B7-2↓ IL-10+TGF-β
human
moDCs
in vitro;
CD1a↑
pre-clinical
MHCⅡ↓
IL-12↓
CD40↓
IL-10↑
(-)
[145, 148]
Type 1 Diabetes
CD83↓ CD86↓ M-CSF
human
moDCs
in vitro;
CD1a↓,
MHCⅡ↓
TNF-α↓
CD40↓
IL-12↓ IL-10↑
CXCR4↓
Reduce T cell
Immune-mediated
priming
diseases
[248]
Agents
Species
DC origin
Vitro/vivo
DC functions
Targeted Diseases
References
Reduce T cell
Immune-mediated
[249]
priming
diseases
More Treg cell
EAE
Study Differentiation
IL-21
human
moDCs
in vitro;
endocytosis↑,
Phenotypic
Cytokine
maturation
production
MHCⅡ↓
TNF-α↓
CD80↓
IL-12↓
Migration
T Cell stimulation
CCR7↓
IL-6↓ IL-1β↓ TNF-α
IFN-β
mouse
mouse
BMDCs
BMDCs
In vivo
in vitro
(-)
(-)
CD40↑
IL-12↓
CD80↑
IL-6↓
Generation, and
CD86↑
IL-1β↓
Reduce T cell
IL-10↑
priming
CD40↑ CD80↑
(-)
(-)
CCR7↓
[250]
[251]
MMP-9↓
CD86↑
moDC, monocyte-derived DC; BMDC, bone marrow-derived DC; MHC II, major histocompatibility class II molecules; IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; TGF:transforming growth factor; ICAM, intercellular cell adhesion molecule; CIA: collagen-induced arthritis; EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis.
