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REVIEW
Mechanisms of pathogenesis in allergic asthma: Role of interleukin-23 YANCHUN LI1 AND SHUCHENG HUA2 Departments of 1Pediatric Respiratory Medicine and 2Respiratory Medicine, First Hospital of Jilin University, Changchun, Jilin Province, China
ABSTRACT Asthma is a chronic airway inflammatory disease characterized by intense leukocyte and eosinophilic infiltration accompanied by mucus hypersecretion and tissue hyperresponsiveness. Recent evidence suggests that T-helper (Th)2 cells and their cytokine products orchestrate the pathology of asthma. In addition, Th17 cells are implicated in the pathogenesis of antigeninduced airway inflammation. The Th17 related cytokine interleukin (IL)-23 plays important roles in many immunological diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Several reports describe the role of IL-23 in the pathogenesis of allergic asthma in both human and mice. IL-23 leads to neutrophil infiltration in the airway of asthmatic mice, which is characteristic of severe asthma resulting from Th17 development and subsequently IL-17 secretion. IL-23 can also promote eosinophil infiltration in the airway, which is a hallmark of allergic asthma. These studies suggest that IL-23 could be a promoting factor in the development of allergic asthma and likewise would be a target for asthma therapy. In support of this view, trials of anti-IL-23 therapy have been attempted in human and mouse asthma models with encouraging outcomes. This review presents the role of IL-23 in asthma according to recent clinical trials and animal model studies. The proposed mechanisms of IL-23induced airway inflammation and the agents currently being tested that target IL-23 related pathways are discussed. Key words: airway, asthma, autoimmune, inflammation, interleukin-23.
Abbreviations: AHR, aryl hydrocarbon receptor; BALF, bronchoalveolar lavage fluid; CD, cluster of differentiation; DC, dendritic cell; EPO, eosinophil peroxidase; FcεRI, Fcε receptor I; FEF25–75, forced expiratory flow between 25% and 75% of vital capacity; FEV1, forced expiratory volume in 1 s; FVC, forced vital
Correspondence: Shucheng Hua, Department of Respiratory Medicine, First Hospital of Jilin University, Changchun, Jilin Province 130021, China. Email: [email protected] Received 23 October 2013; invited to revise 21 November 2013 and 15 January 2014; revised 28 December 2013 and 29 January 2014; accepted 19 February 2014 (Associate Editor: Darryl Knight). © 2014 Asian Pacific Society of Respirology
capacity; ICS, inhaled corticosteroid; IFN-γ, γ-interferon; Ig, immunoglobulin; IL, interleukin; IL-17R−/−, IL-17 receptor– deficient mice; IL-23R, IL-23 receptor; mRNA, messenger RNA; OVA, ovalbumin; RNAi, RNA interference; ROR, retinoic acid receptor-related orphan receptor; STAT, signal transducers and activators of transcription; TGF-β, transforming growth factor-β; Th cell, T-helper cell; TNF-α, tumour necrosis factor-α; Treg cell, regulatory T cell.
INTRODUCTION Allergic asthma is a significant public health problem with substantial morbidity and mortality. Approximately 20% of the world’s population suffers from this disease.1 Currently, the prevalence of allergic asthma is increasing globally due to air pollution and other environmental irritants. These environmental exposures are especially evident in developing countries2 where industrialization is progressing rapidly. Chronic airway inflammatory processes result in intense recruitment of activated eosinophils and T-helper (Th)2 lymphocytes at the site of injury and an inappropriate immune response to common allergens.3 Recurrent inflammation and subsequent abnormalities in the tissue repair mechanisms lead to structural changes in the airway wall that manifest the clinically detectable features of epithelial injury, goblet cell hyperplasia, subepithelial thickening, airway hyperplasia and angiogenesis.4 Thus, allergic asthma is characterized as a complex airway remodelling disease.5 While there is currently no cure for asthma, the standard of care for asthma is limited to symptomatic control of disease mediators with potent inhaled corticosteroids (ICS), long-acting β-adrenergic agonists and leukotriene modifiers.6,7 The limitation with current treatment approaches is that disease modification is not possible with all clinical presentations.8 To develop a full understanding of allergic asthma, it is critical to evaluate the molecular functioning and impact of cytokine generation. Cytokines such as interleukin (IL)-4, IL-5 and IL-13 released from Th2 lymphocytes are recognized as important mediators in the orchestration and scope of allergic responses.9 However, Th1/Th17 phenotypes correlate with airway neutrophilic inflammation frequently found in the Respirology (2014) doi: 10.1111/resp.12299
2 lungs of patients with severe asthma or asthma resistant to corticosteroids.10 γ-Interferon (IFN-γ) and IL-17 are the critical mediators produced from Th1/Th17 lymphocytes.11 Th17 lymphocytes originate from cluster of differentiation (CD)161+CD4 T-cell precursors and secrete the cytokine IL-17 to mediate recruitment of neutrophils and induce the release of pro-inflammatory mediators.12 IL-23 is a macrophage and dendritic cell (DC)-derived inflammatory cytokine identified as a member of the IL-12 family of cytokines with pro-inflammatory properties. IL-23 has the capacity to potently enhance the differentiation of Th17 cells,13,14 suggesting an involvement in the generation of several inflammatory autoimmune disorders. Recent studies have indicated that IL-23 has a variety of biological functions, including the promotion of memory T-cell proliferation,15 DC cytokine production and antigen peptide presentation.16 Therefore, IL-23 plays an important role in various disease processes, such as cancer,17 infectious disease,18,19 autoimmune disease20 and allergic bronchial asthma.21 In this review, we discuss physiological and pathophysiological events relating to the role of IL-23 in inflammation and allergic asthma that can be targeted to help remediate symptoms produced from excessive IL-23 production.
CD4+ Th LYMPHOCYTES AND ALLERGIC ASTHMA Recent studies have shown that DC, which are powerful antigen presenting cells, can be important mediators of allergic asthma. Resident DC in the mucosal tissues of lungs are referred to as ‘immature’. DC are activated and ‘matured’ upon encounter of non-infectious environmental antigens such as dust mite, cigarette smoke, soot and cockroaches.22 The activation occurs via interaction between pathogenassociated molecular patterns found on the antigen and pathogen recognition receptors that are found on the surface of antigen presenting cells.23 Matured DC then modulate the capacity for antigen uptake and concurrently migrate to the draining lymph nodes to activate antigen-specific naïve Th cells and drive their development into effector Th cells, such as Th1, Th2, Th17 or regulatory T (Treg) cells and mediate immunoglobulin (Ig)E isotype switching in B-cells.24 Antigen-specific IgE bind to the high-affinity Fcε receptor I (FcεRI) on mast basophils and mast cells in the airway, thereby leading to receptor aggregation.25 Upon the sufficient strength and duration of aggregation of surface FcεRI, basophils and mast cells initiate complex signalling events that ultimately result in the secretion of a diverse group of biologically active products such as histamine, serotonin and certain cytokines to augment local allergic responses and cause most of the typical clinical symptoms.26
Subtype of CD4+ Th lymphocytes CD4+ Th lymphocytes are a heterogeneous population of cells critical for B-cell antibody production in Respirology (2014)
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the humoral immunity. T cells are also important in the process of activating macrophages, effector cells and Treg in the cell-mediated immune response to foreign material. Several subsets of Th cells have been recognized over the past two decades. Th1 cells are important for cellular immunity, whereas Th2 cells enhance the humoral response.27,28 Cytokines secreted from Th lymphocytes are essential mediators for a number of immune-mediated diseases, including chronic obstructive pulmonary disease and asthma. Evidence from clinical observations and from studies on experimental animals suggests that Th2 cells are involved in the pathogenesis of allergic diseases such as asthma that result from production of IL-4, IL-5 and IL-13.29–33Th2 cells are also intimately involved in inducing IgE class switch in B-lymphocytes and the sensitization of mast cells and basophils.26 A large body of experimental evidence supports the hypothesis that an imbalance between Th1 and Th2 cells or their products is a putative cause of many inflammatory diseases. Infante-Duarte et al. identified an IL-17A-producing CD4+ Th cell subtype (Th17 cells) that was different from the classic Th1 cell and Th2 cell subsets.34
Role of Th17 cells in asthma Th17 cells originate from CD161+CD4 T-cell precursors. Detection of these cell types was conducted, and the presence in both human umbilical cord blood and thymus was confirmed via flow cytometric analysis.35,36 The differentiation of Th17 cells depends on the expression of the classical pro-inflammatory cytokines, IL-1β, IL-23, IL-, and transforming growth factor-β (TGF-β). Th17 cells are characterized by production of a series of pro-inflammatory cytokines, including IL-17A, IL-17F, IL-8, IL-21, IL-22, IL-23, IL-26 and tumour necrosis factor (TNF)-α.37 Activated Th17 cells directly recruit neutrophils via the release of biologically active IL-836 and are indirectly induced by IL-17 expression to clear extracellular pathogens.37 In addition, the retinoic acid receptor-related orphan receptor (ROR) is one of the key transcription factors involved in the generation of Th17 cells. Th17 cells that express RORγt play crucial roles in the induction of autoimmune tissue injuries and inflammation. Schnyder-Candrian et al. demonstrated that the Th2 response (eosinophil recruitment) is markedly impaired in IL-17 receptor–deficient (IL-17R−/−) mice38 and suggested that the IL-17/Th17 axis plays a major role in the recruitment and activation of eosinophils. Still other studies showed that the IL-17/ Th17 axis also induces neutrophil recruitment at the site of infection and inflammation39,40 by inducing granulopoiesis, neutrophil chemotaxis and the antiapoptotic properties of granulocyte colonystimulating factor.41 Tissue damage is mediated not only by the production of cytokines such as IL-17, TNF-α and IL-6, but also via the expression of surface IL-23 receptor (IL-23R).11 Previous studies have indicated that IL-23 is an essential driver in the differentiation of Th17 cells. Data have confirmed that Th17 cells are driven by IL-6 and IL-23 to enhance proliferation of Th17 cells and maintain IL-17 A/F © 2014 Asian Pacific Society of Respirology
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production in both an innate and adaptive capacity instead of promoting differentiation.42 In asthmatic patients, the quantity of Th17 cells is increased in peripheral blood resulting in increased IL-17A/F expression in the lungs, sputum, bronchoalveolar lavage fluids (BALF) and sera.43 Of note, within the IL-17 family of proteins, IL-17A and IL-17F are most closely associated with asthma severity and pulmonary neutrophil recruitment.44 For example, the messenger RNA (mRNA) and protein levels of IL-17A are increased in lung tissue of patients with severe asthma, which was correlated with increased aryl hydrocarbon receptor (AHR) expression in patients with asthma.44 Increased IL-17 expression was also shown in an ovalbumin (OVA)-sensitized mouse model.45 However, Th17-induced neutrophilic inflammation was not affected by steroid treatment in vitro8 or in allergic airway disease of mice,46 so elevated levels of Th17 cells was suggested to be insensitive to glucocorticosteroid treatment.46
IL-23 AND IL-23 RECEPTOR The expression and stability of IL-17 cytokines is regulated by IL-23. IL-23 is a covalently linked heterodimeric haemopoietic cytokine belonging to the IL-12 cytokine family. IL-23 is composed of p40, a subunit of IL-12 and a p19 subunit that is unique to IL-2314 and considered a key component of the immune-regulatory pathway by binding to IL-23R. The IL-23R gene is located on chromosome 1p31 and highly expressed on T cells (mainly expressed on Th17 cells), NK cells, monocytes and DC.47 IL-23R is a heterodimeric receptor composed of IL-12 receptor β1 and IL-23R.14 In recent years, the association between IL-23R and inflammatory diseases has been extensively studied. Accumulating evidence shows that IL-23 receptor complex conveys the IL-23 signal to Th and subsequently activates Janus kinase-2/ signal transducers and activators of transcription (STAT) signal pathway to play a pivotal role in the differentiation and maintenance of Th17 cells.48 Furthermore, many pathological defects found in animal models of autoimmunity are initially caused by IL-23.49 Targeting of IL-23 can be accomplished in several ways to mitigate the effect on disease. First, inhibition of IL-23 via antibodies against the p40 subunit of IL-23/IL-12 or with anti-IL-23 can neutralize the effect of IL-23 in vivo. Alternatively, genetic inactivation of the IL-23p19 gene was effective in controlling both inflammatory and autoimmune disease by reducing IL-17 production.50,51 It is clear that IL-23 and Th17 cells are two critical players in the development of autoimmune diseases and in causing airway inflammation, especially in the context of severe asthma.52 However, with deepening of researches, the role of IL-23 in Th17 cell differentiation remains controversial.53 In mice, following activation of STAT3 and induction of IL-23R expression, Th17 cell differentiation was initiated by IL-6 and TGF-β.54 The mechanisms in humans, however, are not the same. The expression of IL-23R on naïve human T cells and Th17 cells results in a differentiation profile that is intrinsi© 2014 Asian Pacific Society of Respirology
cally different from murine Th17.21 Recently, Ciprandi et al. reported that neither IL-6 nor IL-23 alone can efficiently induce IL17A mRNA. They demonstrated that there was a requirement for IL-6, IL-1β and IL-23 to effectively induce IL17A transcription and protein expression in naïve precursors that was independent of TGF-β55 expression. In addition, IL-23 may enhance antigen-induced Th2 cell differentiation in IL-17R−/− mice40 to regulate Th2 responses.56
IL-23 AND HUMAN ALLERGIC ASTHMA Increased levels of IL-23 and decreased mean forced expiratory volume in the 1 s (FEV1) values have been detected in asthmatic children.57,58 More importantly, a strong inverse relationship between IL-23 and FEV1 has been demonstrated.58 ICS treatment was capable of reducing the level of serum IL-23 and improving overall lung function.57 FEV1, however, is not the best indicator of lung function because it does not respond well to treatment. The actual measure of lung function and relative FEV1, FEV1/forced vital capacity (FVC) ratio and forced expiratory flow between 25% and 75% of vital capacity (FEF25–75) is a more appropriate response index of bronchial airflow. This is especially evident during the plateau of asthma, especially in children, where FEV1 is most likely to be found clinically in the normal range. For this reason, Ciprandi et al. monitored patient serum levels of IL-23 and FEV1/FVC of FEF25–75, and showed that there was still a strong and inverse relationship between serum IL-23 level and FEV1/FVC ratio, as well as FEF25–75 values.57 Based on these recent results, serum IL-23 can be used as an adjunctive surrogate biomarker in assessing asthma severity and airflow obstruction.58
MECHANISM OF IL-23 IN ALLERGIC ASTHMA Excessive production of IL-23 in allergic airway inflammation has recently been confirmed in a murine asthma model. Simultaneously, OVA challenge-induced asthmatic inflammation of mice could be reversed by inhibition of the IL-23 signalling pathway.59
IL-23 modulates Th2 cell differentiation and promotes eosinophil infiltration Although the role of IL-17 in eosinophil recruitment remains controversial, excess generation of IL-23 or transgenic overexpression of IL-23 receptor60 have been shown to exacerbate allergen-induced inflammation through increased Th2 cell and eosinophil activity. Additionally, in vitro IL-23 deprivation was shown to lead to conversion of IL-17 producing cells to the IFN-γ secreting Th1 phenotype.61 In a recent study, data showed that both IL-23-specific p19 mRNA and IL-23R mRNA levels were highly induced within the lungs. These findings were derived from OVA challenged mice and dramatically decreased the Respirology (2014)
4 expression of eosinophil peroxidase (EPO) in IL-23 knock-out mice compared with wild type mice.58 In contrast, markedly elevated EPO expression in the lungs of IL-23R transgenic mice was observed.58 Consistent with these results, Haworth et al. have recently indicated that an endogenous lipid mediator, resolvin E1, also inhibited the development of allergic airway inflammation by inhibiting the IL-23 levels in the
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lung.60 Ishizuka et al. also demonstrated that intravenous administration of RvE1 to a mouse asthma model during the challenge phase and resolution phase dampened the development of allergic airway inflammation by inhibiting the release of IL-23, IL-6 and TNF from lipopolysaccharide-stimulated DC.62 Together these findings suggest that a substantial role for IL-23 in eosinophilic airway inflammation is likely.
(a)
(b)
Figure 1 Dynamic schematic of the role of interleukin (IL)-23. (a) Upon stimulation, mature dendritic cell (DC) activate naïve T-helper (Th) cells and drive their development into effector Th cells, such as Th1, Th2, Th17 or regulatory T cells (Treg).Th17 cells secrete several effector molecules, including IL-6, IL-17A/F, IL-23 and transforming growth factor-β (TGF-β). (b) IL-23 enhances the development and maintenance of Th17 cells and the recruitment of eosinophils and neutrophils into the airways. Moreover, IL-23 stimulates the proliferation of bronchial fibroblasts, epithelial cells and smooth muscle cells. Finally, the IL-23-Th17 axis plays a crucial role in the development of severe, corticosteroid-dependent asthma. ( ) IL-23, ( ) IL-23R. FEF25–75, forced expiratory flow between 25% and 75% of vital capacity; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IFN-γ, γ-interferon; IL-23R, IL-23 receptor. Respirology (2014)
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IL-23 contributes to neutrophil recruitment In addition to eosinophilic inflammation, neutrophilic infiltration is involved in the pathogenesis of the severe asthma.63 Several lines of evidence suggest that increased sputum neutrophil counts and increased release of eosinophil-derived mediators positively correlates with severe, corticosteroiddependent asthma.64 Neutrophilic airway inflammation has been shown to be induced by IL-17A and IL-17F65 expression. Importantly, IL-17, especially IL-17A (155 amino acids), not only promotes eosinophilic airway inflammation by mounting allergenspecific Th2 cell responses at the sensitization phase, but also inhibits eosinophilic airway inflammation by suppressing the local allergic response at the effector phase.56 Moreover, in mice lacking IL-17A, IL-23mediated enhancement of antigen-induced Th2 cytokine production and eosinophil recruitment in the airways was still observed.66 In addition, Bellini et al. recently reported that IL-17A is capable of promoting fibrocyte proliferation and increasing α-smooth muscle actin expression in fibrocytes, and that these responses are dependent on the local concentration of Th2- and Th17-derived cytokines.64 Therefore, IL-17 has been demonstrated to play a vital role in production and recruitment of neutrophils and in stimulating the proliferation of bronchial fibroblasts, epithelial cells and smooth muscle cells. The result of this increased cellular proliferation is an increase in the expression of a variety of cytokines and chemokines. Moreover, a C3a-mediated IL-23/Th17 axis, which leads to IL-17 production, may be critical for the development of the late-phase asthmatic response and AHR in this IgE-sensitized animal model.67 Indeed, the maintenance of the Th17 lineage relied on IL-23 level. In the initial phase, the expression of IL-23R was upregulated in Th17 cells and was promoted by the expression of IL-23. In the final stabilizing state, typical Th17 effector cytokines were produced.68 At present, IL-23-Th17 axis has been recognized as an inflammatory pathway that plays an important role in many diseases, such as Crohn’s disease,49 arthritis68 and allergic airway inflammation.69 Furthermore, a recent study from Li et al. has demonstrated that IL-23-associated Th17 responses contribute to the pathogenic process of bronchial asthma.70 They further demonstrated that higher IL-23 transcription was present in the lungs of asthmatic mice. Inhalation of the IL-23-specific RNA interference (RNAi)-expressing pSRZsi-IL-23p19 plasmid significantly reduced the levels of IL-23 in lung tissue by nearly 75%. Meanwhile, the numbers of eosinophils and neutrophils in BALF were dramatically reduced as well. The anti-inflammatory effects of RNAi expression were similar to or better than that of treatment with budesonide in asthmatic mice. Guan et al. has also demonstrated that targeting the IL-23/ Th17 pathway with long-lasting autoantibodies to IL-23 (IL-23p40 peptide-based vaccine) was successful in reducing airway inflammation in mice, the numbers of total cells, neutrophils, eosinophils and the levels of IL-13, IL-5, IL-23 and IL-17 in BALF, and levels of serum OVA-specific IgE, IgG1 and total IgE71 © 2014 Asian Pacific Society of Respirology
were reduced. Together, these studies suggest that IL-23 could be used as a therapeutic target to decrease allergic airway inflammation in asthma by administration of the IL-23-specific RNAi plasmid or IL-23p40 peptide-based vaccine. Moreover, Liu et al. documented that IL-23 positively correlated with the degree of subepithelial collagen deposition in inferior turbinate mucosa of allergic rhinitis patients.72 However, the precise relationship between IL-23 and airway remodelling in asthma patients still requires further study. Future studies examining the remodelling aspects of IL-23 expression will advance this important area or investigation.
CONCLUSION Our postulated model of the role of IL-23 in the pathogenesis of asthma is shown in Figure 1. Treatment of severe, corticosteroid-dependent asthma remains a substantial clinical challenge. Neutrophil infiltration has emerged as a promising molecular target for treatment of this condition. The mechanism of IL-23 action in asthma not only involves mediation of Th2 cytokines production and eosinophil infiltration independent of IL-17, but also the promotion of Th17 cells’ proliferation to maintain IL-17 A/F production and neutrophil recruitment. Therefore, as a novel therapeutic target, the IL-23/Th17 axis has become a focus of research aiming to develop effective asthma therapies, especially for the severe, corticosteroid-dependent type of asthma.
Acknowledgements The authors report that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this publication. This work was supported by a grant from the National Nature Science Foundation of China (No. 81100014).
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mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J. Immunol. 2008; 181: 4089–97. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 2002; 168: 5699–708. McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O’Shea JJ, Cua DJ. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T-helper cells in vivo. Nat. Immunol. 2009; 10: 314–24. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421: 744–8. Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, Dolin B, Goodman N, Groden C, Hornung RL et al., Anti-IL-12 Crohn’s Disease Study Group. Anti-interleukin-12 antibody for active Crohn’s disease. N. Engl. J. Med. 2004; 351: 2069–79. Krueger GG, Langley RG, Leonardi C, Yeilding N, Guzzo C, Wang Y, Dooley LT, Lebwohl M, CNTO 1275 Psoriasis Study Group. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 2007; 356: 580–92. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T-cell population that induces autoimmune inflammation. J. Exp. Med. 2005; 201: 233–40. McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity 2008; 28: 445–53. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T-cells. Immunity 2006; 24: 179–89. de Jong E, Suddason T, Lord GM. Translational mini-review series on Th17 cells: development of mouse and human T-helper 17 cells. Clin. Exp. Immunol. 2010; 159: 148–58. Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N et al. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature 2010; 467: 967–71. Mizutani N, Goshima H, Nabe T, Yoshino S. Complement C3ainduced IL-17 plays a critical role in an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness via neutrophilic inflammation in mice. J. Immunol. 2012; 188: 5694– 705. Ciprandi G, Cuppari C, Salpietro AM, Tosca MA, Rigoli L, Grasso L, La Rosa M, Marseglia GL, Del Giudice MM, Salpietro C. Serum IL-23 strongly and inversely correlates with FEV1 in asthmatic children. Int. Arch. Allergy Immunol. 2012; 159: 183–6. Ciprandi G, Cuppari C, Salpietro C. Serum IL-23: a surrogate biomarker for asthma? Clin. Exp. Allergy 2012; 42: 1416–17. Peng J, Yang XO, Chang SH, Yang J, Dong C. IL-23 signaling enhances Th2 polarization and regulates allergic airway inflammation. Cell Res. 2010; 20: 62–71.
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7 60 Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD. Resolvin E 1 regulates interleukin 23, interferon-γ and lipoxin A 4 to promote the resolution of allergic airway inflammation. Nat. Immunol. 2008; 9: 873–9. 61 Taherian M, Razavi AR, Izad M, Boghozian R, Namdari H, Ghayedi M, Rahimzadeh P, Bidad K, Salehi E. The role of interleukin-23 in stability of in vitro T helper-17 cells. Iran. J. Allergy Asthma Immunol. 2014; 13: 131–7. 62 Ishizuka T, Hisada T, Aoki H, Mori M. Resolvin E1: a novel lipid mediator in the resolution of allergic airway inflammation. Expert Rev. Clin. Immunol. 2008; 4: 669–72. 63 Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am. J. Respir. Crit. Care Med. 1999; 160: 1001–8. 64 Bellini A, Marini MA, Bianchetti L, Barczyk M, Schmidt M, Mattoli S. Interleukin (IL)-4, IL-13, and IL-17A differentially affect the profibrotic and proinflammatory functions of fibrocytes from asthmatic patients. Mucosal. Immunol. 2012; 5: 140–9. 65 Kikuchi S, Nagata M, Kikuchi I, Hagiwara K, Kanazawa M. Association between neutrophilic and eosinophilic inflammation in patients with severe persistent asthma. Int. Arch. Allergy Immunol. 2005; 137: 7–11. 66 Oda N, Canelos PB, Essayan DM, Plunkett BA, Myers AC, Huang SK. Interleukin-17F induces pulmonary neutrophilia and amplifies antigen-induced allergic response. Am. J. Respir. Crit. Care Med. 2005; 171: 12–18. 67 Wakashin H, Hirose K, Maezawa Y, Kagami S, Suto A, Watanabe N, Saito Y, Hatano M, Tokuhisa T, Iwakura Y et al. IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. Am. J. Respir. Crit. Care Med. 2008; 178: 1023–32. 68 Cornelissen F, van Hamburg JP, Lubberts E. The IL-12/IL-23 axis and its role in Th17 cell development, pathology and plasticity in arthritis. Curr. Opin. Investig. Drugs 2009; 10: 452–62. 69 McGee HS, Stallworth AL, Agrawal T, Shao Z, Lorence L, Agrawal DK. Fms-like tyrosine kinase 3 ligand decreases T helper type 17 cells and suppressors of cytokine signaling proteins in the lung of house dust mite-sensitized and -challenged mice. Am. J. Respir. Cell Mol. Biol. 2010; 43: 520–9. 70 Li Y, Sun M, Cheng H, Li S, Liu L, Qiao H, Hua S, Lu J. Silencing IL-23 expression by a small hairpin RNA protects against asthma in mice. Exp. Mol. Med. 2011; 43: 197–204. 71 Guan Q, Ma Y, Aboud L, Weiss CR, Qing G, Warrington RJ, Peng Z. Targeting IL-23 by employing a p40 peptide-based vaccine ameliorates murine allergic skin and airway inflammation. Clin. Exp. Allergy 2012; 42: 1397–405. 72 Liu Y, Liu Z, Lu X, Gao Q, Cui Y. The expression of IL-23 in nasal mucosa of allergic rhinitis patients and its significance [Article in Chinese]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2010; 24: 638–40.
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REVIEW
Mechanisms of pathogenesis in allergic asthma: Role of interleukin-23 YANCHUN LI1 AND SHUCHENG HUA2 Departments of 1Pediatric Respiratory Medicine and 2Respiratory Medicine, First Hospital of Jilin University, Changchun, Jilin Province, China
ABSTRACT Asthma is a chronic airway inflammatory disease characterized by intense leukocyte and eosinophilic infiltration accompanied by mucus hypersecretion and tissue hyperresponsiveness. Recent evidence suggests that T-helper (Th)2 cells and their cytokine products orchestrate the pathology of asthma. In addition, Th17 cells are implicated in the pathogenesis of antigeninduced airway inflammation. The Th17 related cytokine interleukin (IL)-23 plays important roles in many immunological diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Several reports describe the role of IL-23 in the pathogenesis of allergic asthma in both human and mice. IL-23 leads to neutrophil infiltration in the airway of asthmatic mice, which is characteristic of severe asthma resulting from Th17 development and subsequently IL-17 secretion. IL-23 can also promote eosinophil infiltration in the airway, which is a hallmark of allergic asthma. These studies suggest that IL-23 could be a promoting factor in the development of allergic asthma and likewise would be a target for asthma therapy. In support of this view, trials of anti-IL-23 therapy have been attempted in human and mouse asthma models with encouraging outcomes. This review presents the role of IL-23 in asthma according to recent clinical trials and animal model studies. The proposed mechanisms of IL-23induced airway inflammation and the agents currently being tested that target IL-23 related pathways are discussed. Key words: airway, asthma, autoimmune, inflammation, interleukin-23.
Abbreviations: AHR, aryl hydrocarbon receptor; BALF, bronchoalveolar lavage fluid; CD, cluster of differentiation; DC, dendritic cell; EPO, eosinophil peroxidase; FcεRI, Fcε receptor I; FEF25–75, forced expiratory flow between 25% and 75% of vital capacity; FEV1, forced expiratory volume in 1 s; FVC, forced vital
Correspondence: Shucheng Hua, Department of Respiratory Medicine, First Hospital of Jilin University, Changchun, Jilin Province 130021, China. Email: [email protected] Received 23 October 2013; invited to revise 21 November 2013 and 15 January 2014; revised 28 December 2013 and 29 January 2014; accepted 19 February 2014 (Associate Editor: Darryl Knight). © 2014 Asian Pacific Society of Respirology
capacity; ICS, inhaled corticosteroid; IFN-γ, γ-interferon; Ig, immunoglobulin; IL, interleukin; IL-17R−/−, IL-17 receptor– deficient mice; IL-23R, IL-23 receptor; mRNA, messenger RNA; OVA, ovalbumin; RNAi, RNA interference; ROR, retinoic acid receptor-related orphan receptor; STAT, signal transducers and activators of transcription; TGF-β, transforming growth factor-β; Th cell, T-helper cell; TNF-α, tumour necrosis factor-α; Treg cell, regulatory T cell.
INTRODUCTION Allergic asthma is a significant public health problem with substantial morbidity and mortality. Approximately 20% of the world’s population suffers from this disease.1 Currently, the prevalence of allergic asthma is increasing globally due to air pollution and other environmental irritants. These environmental exposures are especially evident in developing countries2 where industrialization is progressing rapidly. Chronic airway inflammatory processes result in intense recruitment of activated eosinophils and T-helper (Th)2 lymphocytes at the site of injury and an inappropriate immune response to common allergens.3 Recurrent inflammation and subsequent abnormalities in the tissue repair mechanisms lead to structural changes in the airway wall that manifest the clinically detectable features of epithelial injury, goblet cell hyperplasia, subepithelial thickening, airway hyperplasia and angiogenesis.4 Thus, allergic asthma is characterized as a complex airway remodelling disease.5 While there is currently no cure for asthma, the standard of care for asthma is limited to symptomatic control of disease mediators with potent inhaled corticosteroids (ICS), long-acting β-adrenergic agonists and leukotriene modifiers.6,7 The limitation with current treatment approaches is that disease modification is not possible with all clinical presentations.8 To develop a full understanding of allergic asthma, it is critical to evaluate the molecular functioning and impact of cytokine generation. Cytokines such as interleukin (IL)-4, IL-5 and IL-13 released from Th2 lymphocytes are recognized as important mediators in the orchestration and scope of allergic responses.9 However, Th1/Th17 phenotypes correlate with airway neutrophilic inflammation frequently found in the Respirology (2014) doi: 10.1111/resp.12299
2 lungs of patients with severe asthma or asthma resistant to corticosteroids.10 γ-Interferon (IFN-γ) and IL-17 are the critical mediators produced from Th1/Th17 lymphocytes.11 Th17 lymphocytes originate from cluster of differentiation (CD)161+CD4 T-cell precursors and secrete the cytokine IL-17 to mediate recruitment of neutrophils and induce the release of pro-inflammatory mediators.12 IL-23 is a macrophage and dendritic cell (DC)-derived inflammatory cytokine identified as a member of the IL-12 family of cytokines with pro-inflammatory properties. IL-23 has the capacity to potently enhance the differentiation of Th17 cells,13,14 suggesting an involvement in the generation of several inflammatory autoimmune disorders. Recent studies have indicated that IL-23 has a variety of biological functions, including the promotion of memory T-cell proliferation,15 DC cytokine production and antigen peptide presentation.16 Therefore, IL-23 plays an important role in various disease processes, such as cancer,17 infectious disease,18,19 autoimmune disease20 and allergic bronchial asthma.21 In this review, we discuss physiological and pathophysiological events relating to the role of IL-23 in inflammation and allergic asthma that can be targeted to help remediate symptoms produced from excessive IL-23 production.
CD4+ Th LYMPHOCYTES AND ALLERGIC ASTHMA Recent studies have shown that DC, which are powerful antigen presenting cells, can be important mediators of allergic asthma. Resident DC in the mucosal tissues of lungs are referred to as ‘immature’. DC are activated and ‘matured’ upon encounter of non-infectious environmental antigens such as dust mite, cigarette smoke, soot and cockroaches.22 The activation occurs via interaction between pathogenassociated molecular patterns found on the antigen and pathogen recognition receptors that are found on the surface of antigen presenting cells.23 Matured DC then modulate the capacity for antigen uptake and concurrently migrate to the draining lymph nodes to activate antigen-specific naïve Th cells and drive their development into effector Th cells, such as Th1, Th2, Th17 or regulatory T (Treg) cells and mediate immunoglobulin (Ig)E isotype switching in B-cells.24 Antigen-specific IgE bind to the high-affinity Fcε receptor I (FcεRI) on mast basophils and mast cells in the airway, thereby leading to receptor aggregation.25 Upon the sufficient strength and duration of aggregation of surface FcεRI, basophils and mast cells initiate complex signalling events that ultimately result in the secretion of a diverse group of biologically active products such as histamine, serotonin and certain cytokines to augment local allergic responses and cause most of the typical clinical symptoms.26
Subtype of CD4+ Th lymphocytes CD4+ Th lymphocytes are a heterogeneous population of cells critical for B-cell antibody production in Respirology (2014)
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the humoral immunity. T cells are also important in the process of activating macrophages, effector cells and Treg in the cell-mediated immune response to foreign material. Several subsets of Th cells have been recognized over the past two decades. Th1 cells are important for cellular immunity, whereas Th2 cells enhance the humoral response.27,28 Cytokines secreted from Th lymphocytes are essential mediators for a number of immune-mediated diseases, including chronic obstructive pulmonary disease and asthma. Evidence from clinical observations and from studies on experimental animals suggests that Th2 cells are involved in the pathogenesis of allergic diseases such as asthma that result from production of IL-4, IL-5 and IL-13.29–33Th2 cells are also intimately involved in inducing IgE class switch in B-lymphocytes and the sensitization of mast cells and basophils.26 A large body of experimental evidence supports the hypothesis that an imbalance between Th1 and Th2 cells or their products is a putative cause of many inflammatory diseases. Infante-Duarte et al. identified an IL-17A-producing CD4+ Th cell subtype (Th17 cells) that was different from the classic Th1 cell and Th2 cell subsets.34
Role of Th17 cells in asthma Th17 cells originate from CD161+CD4 T-cell precursors. Detection of these cell types was conducted, and the presence in both human umbilical cord blood and thymus was confirmed via flow cytometric analysis.35,36 The differentiation of Th17 cells depends on the expression of the classical pro-inflammatory cytokines, IL-1β, IL-23, IL-, and transforming growth factor-β (TGF-β). Th17 cells are characterized by production of a series of pro-inflammatory cytokines, including IL-17A, IL-17F, IL-8, IL-21, IL-22, IL-23, IL-26 and tumour necrosis factor (TNF)-α.37 Activated Th17 cells directly recruit neutrophils via the release of biologically active IL-836 and are indirectly induced by IL-17 expression to clear extracellular pathogens.37 In addition, the retinoic acid receptor-related orphan receptor (ROR) is one of the key transcription factors involved in the generation of Th17 cells. Th17 cells that express RORγt play crucial roles in the induction of autoimmune tissue injuries and inflammation. Schnyder-Candrian et al. demonstrated that the Th2 response (eosinophil recruitment) is markedly impaired in IL-17 receptor–deficient (IL-17R−/−) mice38 and suggested that the IL-17/Th17 axis plays a major role in the recruitment and activation of eosinophils. Still other studies showed that the IL-17/ Th17 axis also induces neutrophil recruitment at the site of infection and inflammation39,40 by inducing granulopoiesis, neutrophil chemotaxis and the antiapoptotic properties of granulocyte colonystimulating factor.41 Tissue damage is mediated not only by the production of cytokines such as IL-17, TNF-α and IL-6, but also via the expression of surface IL-23 receptor (IL-23R).11 Previous studies have indicated that IL-23 is an essential driver in the differentiation of Th17 cells. Data have confirmed that Th17 cells are driven by IL-6 and IL-23 to enhance proliferation of Th17 cells and maintain IL-17 A/F © 2014 Asian Pacific Society of Respirology
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production in both an innate and adaptive capacity instead of promoting differentiation.42 In asthmatic patients, the quantity of Th17 cells is increased in peripheral blood resulting in increased IL-17A/F expression in the lungs, sputum, bronchoalveolar lavage fluids (BALF) and sera.43 Of note, within the IL-17 family of proteins, IL-17A and IL-17F are most closely associated with asthma severity and pulmonary neutrophil recruitment.44 For example, the messenger RNA (mRNA) and protein levels of IL-17A are increased in lung tissue of patients with severe asthma, which was correlated with increased aryl hydrocarbon receptor (AHR) expression in patients with asthma.44 Increased IL-17 expression was also shown in an ovalbumin (OVA)-sensitized mouse model.45 However, Th17-induced neutrophilic inflammation was not affected by steroid treatment in vitro8 or in allergic airway disease of mice,46 so elevated levels of Th17 cells was suggested to be insensitive to glucocorticosteroid treatment.46
IL-23 AND IL-23 RECEPTOR The expression and stability of IL-17 cytokines is regulated by IL-23. IL-23 is a covalently linked heterodimeric haemopoietic cytokine belonging to the IL-12 cytokine family. IL-23 is composed of p40, a subunit of IL-12 and a p19 subunit that is unique to IL-2314 and considered a key component of the immune-regulatory pathway by binding to IL-23R. The IL-23R gene is located on chromosome 1p31 and highly expressed on T cells (mainly expressed on Th17 cells), NK cells, monocytes and DC.47 IL-23R is a heterodimeric receptor composed of IL-12 receptor β1 and IL-23R.14 In recent years, the association between IL-23R and inflammatory diseases has been extensively studied. Accumulating evidence shows that IL-23 receptor complex conveys the IL-23 signal to Th and subsequently activates Janus kinase-2/ signal transducers and activators of transcription (STAT) signal pathway to play a pivotal role in the differentiation and maintenance of Th17 cells.48 Furthermore, many pathological defects found in animal models of autoimmunity are initially caused by IL-23.49 Targeting of IL-23 can be accomplished in several ways to mitigate the effect on disease. First, inhibition of IL-23 via antibodies against the p40 subunit of IL-23/IL-12 or with anti-IL-23 can neutralize the effect of IL-23 in vivo. Alternatively, genetic inactivation of the IL-23p19 gene was effective in controlling both inflammatory and autoimmune disease by reducing IL-17 production.50,51 It is clear that IL-23 and Th17 cells are two critical players in the development of autoimmune diseases and in causing airway inflammation, especially in the context of severe asthma.52 However, with deepening of researches, the role of IL-23 in Th17 cell differentiation remains controversial.53 In mice, following activation of STAT3 and induction of IL-23R expression, Th17 cell differentiation was initiated by IL-6 and TGF-β.54 The mechanisms in humans, however, are not the same. The expression of IL-23R on naïve human T cells and Th17 cells results in a differentiation profile that is intrinsi© 2014 Asian Pacific Society of Respirology
cally different from murine Th17.21 Recently, Ciprandi et al. reported that neither IL-6 nor IL-23 alone can efficiently induce IL17A mRNA. They demonstrated that there was a requirement for IL-6, IL-1β and IL-23 to effectively induce IL17A transcription and protein expression in naïve precursors that was independent of TGF-β55 expression. In addition, IL-23 may enhance antigen-induced Th2 cell differentiation in IL-17R−/− mice40 to regulate Th2 responses.56
IL-23 AND HUMAN ALLERGIC ASTHMA Increased levels of IL-23 and decreased mean forced expiratory volume in the 1 s (FEV1) values have been detected in asthmatic children.57,58 More importantly, a strong inverse relationship between IL-23 and FEV1 has been demonstrated.58 ICS treatment was capable of reducing the level of serum IL-23 and improving overall lung function.57 FEV1, however, is not the best indicator of lung function because it does not respond well to treatment. The actual measure of lung function and relative FEV1, FEV1/forced vital capacity (FVC) ratio and forced expiratory flow between 25% and 75% of vital capacity (FEF25–75) is a more appropriate response index of bronchial airflow. This is especially evident during the plateau of asthma, especially in children, where FEV1 is most likely to be found clinically in the normal range. For this reason, Ciprandi et al. monitored patient serum levels of IL-23 and FEV1/FVC of FEF25–75, and showed that there was still a strong and inverse relationship between serum IL-23 level and FEV1/FVC ratio, as well as FEF25–75 values.57 Based on these recent results, serum IL-23 can be used as an adjunctive surrogate biomarker in assessing asthma severity and airflow obstruction.58
MECHANISM OF IL-23 IN ALLERGIC ASTHMA Excessive production of IL-23 in allergic airway inflammation has recently been confirmed in a murine asthma model. Simultaneously, OVA challenge-induced asthmatic inflammation of mice could be reversed by inhibition of the IL-23 signalling pathway.59
IL-23 modulates Th2 cell differentiation and promotes eosinophil infiltration Although the role of IL-17 in eosinophil recruitment remains controversial, excess generation of IL-23 or transgenic overexpression of IL-23 receptor60 have been shown to exacerbate allergen-induced inflammation through increased Th2 cell and eosinophil activity. Additionally, in vitro IL-23 deprivation was shown to lead to conversion of IL-17 producing cells to the IFN-γ secreting Th1 phenotype.61 In a recent study, data showed that both IL-23-specific p19 mRNA and IL-23R mRNA levels were highly induced within the lungs. These findings were derived from OVA challenged mice and dramatically decreased the Respirology (2014)
4 expression of eosinophil peroxidase (EPO) in IL-23 knock-out mice compared with wild type mice.58 In contrast, markedly elevated EPO expression in the lungs of IL-23R transgenic mice was observed.58 Consistent with these results, Haworth et al. have recently indicated that an endogenous lipid mediator, resolvin E1, also inhibited the development of allergic airway inflammation by inhibiting the IL-23 levels in the
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lung.60 Ishizuka et al. also demonstrated that intravenous administration of RvE1 to a mouse asthma model during the challenge phase and resolution phase dampened the development of allergic airway inflammation by inhibiting the release of IL-23, IL-6 and TNF from lipopolysaccharide-stimulated DC.62 Together these findings suggest that a substantial role for IL-23 in eosinophilic airway inflammation is likely.
(a)
(b)
Figure 1 Dynamic schematic of the role of interleukin (IL)-23. (a) Upon stimulation, mature dendritic cell (DC) activate naïve T-helper (Th) cells and drive their development into effector Th cells, such as Th1, Th2, Th17 or regulatory T cells (Treg).Th17 cells secrete several effector molecules, including IL-6, IL-17A/F, IL-23 and transforming growth factor-β (TGF-β). (b) IL-23 enhances the development and maintenance of Th17 cells and the recruitment of eosinophils and neutrophils into the airways. Moreover, IL-23 stimulates the proliferation of bronchial fibroblasts, epithelial cells and smooth muscle cells. Finally, the IL-23-Th17 axis plays a crucial role in the development of severe, corticosteroid-dependent asthma. ( ) IL-23, ( ) IL-23R. FEF25–75, forced expiratory flow between 25% and 75% of vital capacity; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IFN-γ, γ-interferon; IL-23R, IL-23 receptor. Respirology (2014)
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IL-23 contributes to neutrophil recruitment In addition to eosinophilic inflammation, neutrophilic infiltration is involved in the pathogenesis of the severe asthma.63 Several lines of evidence suggest that increased sputum neutrophil counts and increased release of eosinophil-derived mediators positively correlates with severe, corticosteroiddependent asthma.64 Neutrophilic airway inflammation has been shown to be induced by IL-17A and IL-17F65 expression. Importantly, IL-17, especially IL-17A (155 amino acids), not only promotes eosinophilic airway inflammation by mounting allergenspecific Th2 cell responses at the sensitization phase, but also inhibits eosinophilic airway inflammation by suppressing the local allergic response at the effector phase.56 Moreover, in mice lacking IL-17A, IL-23mediated enhancement of antigen-induced Th2 cytokine production and eosinophil recruitment in the airways was still observed.66 In addition, Bellini et al. recently reported that IL-17A is capable of promoting fibrocyte proliferation and increasing α-smooth muscle actin expression in fibrocytes, and that these responses are dependent on the local concentration of Th2- and Th17-derived cytokines.64 Therefore, IL-17 has been demonstrated to play a vital role in production and recruitment of neutrophils and in stimulating the proliferation of bronchial fibroblasts, epithelial cells and smooth muscle cells. The result of this increased cellular proliferation is an increase in the expression of a variety of cytokines and chemokines. Moreover, a C3a-mediated IL-23/Th17 axis, which leads to IL-17 production, may be critical for the development of the late-phase asthmatic response and AHR in this IgE-sensitized animal model.67 Indeed, the maintenance of the Th17 lineage relied on IL-23 level. In the initial phase, the expression of IL-23R was upregulated in Th17 cells and was promoted by the expression of IL-23. In the final stabilizing state, typical Th17 effector cytokines were produced.68 At present, IL-23-Th17 axis has been recognized as an inflammatory pathway that plays an important role in many diseases, such as Crohn’s disease,49 arthritis68 and allergic airway inflammation.69 Furthermore, a recent study from Li et al. has demonstrated that IL-23-associated Th17 responses contribute to the pathogenic process of bronchial asthma.70 They further demonstrated that higher IL-23 transcription was present in the lungs of asthmatic mice. Inhalation of the IL-23-specific RNA interference (RNAi)-expressing pSRZsi-IL-23p19 plasmid significantly reduced the levels of IL-23 in lung tissue by nearly 75%. Meanwhile, the numbers of eosinophils and neutrophils in BALF were dramatically reduced as well. The anti-inflammatory effects of RNAi expression were similar to or better than that of treatment with budesonide in asthmatic mice. Guan et al. has also demonstrated that targeting the IL-23/ Th17 pathway with long-lasting autoantibodies to IL-23 (IL-23p40 peptide-based vaccine) was successful in reducing airway inflammation in mice, the numbers of total cells, neutrophils, eosinophils and the levels of IL-13, IL-5, IL-23 and IL-17 in BALF, and levels of serum OVA-specific IgE, IgG1 and total IgE71 © 2014 Asian Pacific Society of Respirology
were reduced. Together, these studies suggest that IL-23 could be used as a therapeutic target to decrease allergic airway inflammation in asthma by administration of the IL-23-specific RNAi plasmid or IL-23p40 peptide-based vaccine. Moreover, Liu et al. documented that IL-23 positively correlated with the degree of subepithelial collagen deposition in inferior turbinate mucosa of allergic rhinitis patients.72 However, the precise relationship between IL-23 and airway remodelling in asthma patients still requires further study. Future studies examining the remodelling aspects of IL-23 expression will advance this important area or investigation.
CONCLUSION Our postulated model of the role of IL-23 in the pathogenesis of asthma is shown in Figure 1. Treatment of severe, corticosteroid-dependent asthma remains a substantial clinical challenge. Neutrophil infiltration has emerged as a promising molecular target for treatment of this condition. The mechanism of IL-23 action in asthma not only involves mediation of Th2 cytokines production and eosinophil infiltration independent of IL-17, but also the promotion of Th17 cells’ proliferation to maintain IL-17 A/F production and neutrophil recruitment. Therefore, as a novel therapeutic target, the IL-23/Th17 axis has become a focus of research aiming to develop effective asthma therapies, especially for the severe, corticosteroid-dependent type of asthma.
Acknowledgements The authors report that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this publication. This work was supported by a grant from the National Nature Science Foundation of China (No. 81100014).
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