Mol Neurobiol DOI 10.1007/s12035-013-8631-3

Crosstalk Between Insulin and Toll-like Receptor Signaling Pathways in the Central Nervous system Fatemeh Hemmati & Rasoul Ghasemi & Norlinah Mohamed Ibrahim & Leila Dargahi & Zahurin Mohamed & Azman Ali Raymond & Abolhassan Ahmadiani

Received: 11 December 2013 / Accepted: 25 December 2013 # Springer Science+Business Media New York 2014

Abstract Neuroinflammation is known as a key player in a variety of neurodegenerative and/or neurological diseases. Brain Toll-like receptors (TLRs) are leading elements in the initiation and progression of neuroinflammation and the development of different neuronal diseases. Furthermore, TLR activation is one of the most important elements in the induction of insulin resistance in different organs such as the central nervous system. Involvement of insulin signaling dysregulation and insulin resistance are also shown to contribute to the pathology of neurological diseases. Considering the important roles of TLRs in neuroinflammation and central insulin resistance and the effects of these processes in the initiation and progression of neurodegenerative and neurological diseases, here we are going to review current knowledge about the potential crosstalk between TLRs and insulin signaling pathways in neuroinflammatory disorders of the central nervous system.

Fatemeh Hemmati and Rasoul Ghasemi contributed equally to this work and should be considered as co-first authors. F. Hemmati : N. Mohamed Ibrahim : A. A. Raymond Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia R. Ghasemi Neuroscience Research Center and Department of Physiology, Shiraz University of Medical Sciences, Shiraz, Iran L. Dargahi : A. Ahmadiani NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran L. Dargahi : A. Ahmadiani Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Z. Mohamed : A. Ahmadiani (*) Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia e-mail: [email protected]

Keywords Insulin . Toll-like receptors . Neuroinflammation

Introduction For several decades, the brain is considered as an immuneprivileged organ which is not affected by the immune system. It is now clear that the central nervous system (CNS) not only has its own immune response mechanisms, but also under appropriate conditions, inflammatory cells and factors could cross the blood-brain barrier (BBB) to access the CNS [1]. However, inflammatory responses in the CNS serve to protect the brain tissue against insulting stimuli, but it could turn into a destructive process [2], to the extent that neuroinflammation is known as a key player in several neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) as well as psychiatric disorders [3–6]. Toll-like receptors (TLRs) are among the most important contributors in the initiation and progression of neuroinflammatory processes. TLRs are a group of glycoproteins that are widely expressed within the CNS and recognize pattern-associated molecular patterns (PAMPs) as well as endogenous danger signals (damageassociated molecular patterns or DAMPs). TLRs play an essential role in the mediation of immune responses and CNS repair and development, and along with these roles, TLRs play a central role in the pathology of different neurological disorders [7, 8]. TLRs are also shown to contribute to the impairment of insulin signaling in different organs including the CNS [9, 10]. Given that insulin signaling plays a central role in the physiological functions of the CNS (reviewed in [11]) and disruption of insulin signaling is a key contributor in the pathology of neurological diseases (reviewed in [12]), hereby we review the latest documents about TLRs and their roles in the physiology and pathology of the CNS, considering its possible interaction with insulin signaling pathway.

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Neuroinflammation Inflammation is defined as a highly regulated biological response to harmful stimuli such as infectious agents and tissue injury which is brought about by activation of resident as well as recruitment of migrating inflammatory cells. Primarily, inflammatory responses play a protective role against invading pathogens; however, it also contributes to the pathology of many chronic diseases [13]. Inflammatory responses are classified into two types—acute and chronic. Whereas acute inflammation is mostly beneficial and allows the inflamed organ to limit the proliferation of invading pathogens and facilitate their clearance, more persistent chronic inflammation could result in pathogenic processes [14]. The presence of tight BBB and the resulting limited entrance of immune cytokines, in addition to a low level of MHC and adhesion molecules and lower rejection of transplants within the CNS, all raised a notion that the CNS is an immune-privileged organ which is not susceptible to inflammation or immune activation. This old concept now has been revolutionized by accumulating evidences showing that the CNS has its own immune susceptibility and it can be affected by immune responses [1, 15]. It is well documented that disruption of BBB and the resulting entrance of immunological mediators accompanied by production and release of these mediators via CNS cells (particularly microglial cells) initiate a more restrictive type of inflammation named as neuroinflammation [1, 16]. Neuroinflammatory responses are shown to be somehow different from the inflammatory response elsewhere. For instance, edema as a typical phenotype of inflammation is limited in the CNS (because of the cranium). Another difference which can be seen in neuroinflammation is the recruitment of leucocytes, which is very rapid in systemic organs, but in the CNS, it is delayed. In spite of this delayed recruitment of leucocytes in the brain, microglial activation and release of inflammatory mediators are shown to be rapid (reviewed in [1]). Mechanisms: Cells, Receptors, and Mediators Several types of cells within the CNS are shown to be involved in the initiation and regulation of immune responses. These cells are categorized into two groups: (1) residential cells such as microglia, astrocytes, and endothelial cells and (2) infiltrating cells such as T cells and macrophages [15]. Similar to inflammatory responses in extraneuronal organs, neuroinflammatory responses are also elicited by both exogenous and endogenous stimuli, and recognition of these stimuli and triggering of inflammatory responses in the CNS is carried out through different classes of receptors. Pattern Recognition Receptors (PRRs) These are activated by pathogen-associated molecular patterns (PAMPs) derived

from exogenous stimuli (such as lipopolysaccharide (LPS), viral double-stranded RNA) and endogenously derived molecules (such as components of necrotic cells and molecules formed by pathogenic mechanisms). TLRs are one class of this receptor family. These receptors are expressed widely in CNS cells and play a role in the physiology and pathophysiology of the CNS (TLRs will be described in the succeeding sections) [17]. Purinergic Receptors These receptors are expressed on microglia and astrocytes and are activated by ATP released from injured and/or dead cells [18]. Scavenger Receptors Different cell types in the CNS including microglia and astrocytes express these receptors, and they participate in the uptake of both native and pathologically modified substances and play a role in host defense against bacterial pathogens [19]. Under physiological conditions, microglial cells “as the main cellular component of CNS immune response” are in inactive form, and upon detection of danger signals (either pathogen invasion or tissue damage), these cells switch to their active immunological form which releases inflammatory mediators (e.g., IL-1β, TNF-α). Secretion of these cytokines from microglia ultimately leads to activation of astrocytes and secondary inflammatory response will be ignited in the CNS [20, 21]. If the acute inflammatory response fails to resolve the stimulus and/or the inflammatory stimuli persists for a longer time, feed-forward loops would be started and its resulting uncontrolled neuroinflammatory response would leave detrimental effect on the CNS, a process which could be seen in many neurodegenerative and neurological diseases [20].

Toll-like Receptors Toll-like receptors (TLRs) are a family of type I transmembrane glycoproteins which play an essential role in the immune system. Structurally, TLRs are characterized by a number of leucine-rich repeats (LRR) in the extracellular domain which participate in the ligand recognition, followed by a LRR carboxy-terminal domain which separates LRR from the transmembrane domain and a conserved intracellular Toll/IL-1 receptor (TIR) domain [22]. The primary function of TLRs as PRRs is the detection of specific molecular patterns named as PAMPs. PAMPs sensed by TLRs are structural components (such as lipids, proteins, lipoproteins, and nucleic acids) derived from bacteria, viruses, fungi, and parasites [23, 24]. TLRs also take part in the recognition of endogenous ligands mainly derived from tissue damage and cellular stress, and these ligands are known as danger (damage)-associated molecular patterns (DAMPs). By this way, TLRs participate in sterile inflammatory responses observed in various pathological processes [25].

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To date, 10 and 13 members of TLRs have been identified in human and mouse. The majority of these members (TLR1–9) are conserved in both species, and TLR11, 12, and 13 are only present in the mouse genome, while TLR10 seems to be an inactive form [24]. Based on their subcellular localization, TLRs are categorized into two groups: a group consisting of TLR1, 2, 4, 5, 6, and 11 which are expressed on the cell surface and mainly senses membrane-derived structures such as lipids, lipoproteins, and proteins. Another group including TLR3, 7, 8, and 9 is present in the intracellular compartments such as the endoplasmic reticulum (ER), endosomes, and endolysosomes and recognizes bacterial or virus nucleic acids. This subcellular localization is mainly determined by transmembrane and membrane-proximal regions of TLRs [26]. It has been shown that recognition of different ligands is carried out via different members of the TLR family. While TLR2/TLR1 dimer senses bacterial triacylated lipopeptides, the TLR2/TLR6 dimer is responsible for the recognition of diacylated lipopeptides. In such a way, TLR3 detects doublestranded RNA (dsRNA), TLR4 is mainly specific for LPS and host-derived ligands such as HSPs and fibronectin, TLR5 senses bacterial flagellin, TLR7 and TLR 8 act as sensor for single-stranded RNAs (ssRNA), and finally, nonmethylated cytosine guanosine (CPG) DNAs are recognized by TLR9. Host-derived ligands such as HSPs and fibronectin, saturated fatty acids, oligosaccharides of hyaluronic acid, and polysaccharide fragments of heparin sulfate are mainly detected by TLR4 and TLR2 [26–29].

associated kinase (IRAK1 and 4) and phosphorylation of both IRAK1 and 4. IRAK1 and IRAK4 phosphorylation then causes an active oligomer between IRAKs and tumor necrosis factor receptor-associated factor-6 (TRAF-6) to be formed. TRAF-6 in turn activates transforming growth factor-β-activated protein kinase 1 (TAK1), and in the next step, TAK1 forms a complex with TAK1-binding protein (TAB1, 2, and 3) and activates Ik B kinase (IKK). Activated IKK would be able to induce phosphorylation of Ik B, tagging it for degradation. Once Ik B is degraded, NF-ĸB is freed to enter the nucleus and initiates the transcription of various inflammatory genes. Concurrent with the activation of IKK, TAK1 also phosphorylates two members of the MAP kinase kinase family (MKK3 and MKK6), and by this pathway, P38 and JNK mitogen-activated protein kinases (MAPKs) are activated by TLRs. Subsequently, P38 and JNK translocate to the nucleus and initiate the transcription of activator protein-1 (AP1) and c-Jun target genes (Fig. 1). TLRs also activate the third member of the MAPK family (ERK) through MEK1 and MEK2, but the exact pathway linking TLRs to MEK/ERK activation remains to be elucidated (reviewed in [29, 32]). MyD88-independent pathway is carried out via another adaptor protein, TRIF. In this pathway, TRIF binds simultaneously to TRAF-6 and receptor interacting protein (RIP) and this ultimately leads to NF-ĸB and JNK activation. TRIF binding to TLR3 also initiates another MyD88-independent pathway which is carried out via recruitment of TRAF3 and subsequent activation of TRAF-associated NF-ĸB activator (TANK) binding kinase (TBK1), and this kinase then phosphorylates interferon regulatory factors (IRF), finally leading to interferon release. In this way, cells try to fight against the virus that activated TLR3 (reviewed in [32]) (Fig. 2).

TLR Signaling Pathway

TLR Interaction with Insulin Signaling Pathway

When TLRs bind to their ligands, the first step in the initiation of intracellular signaling pathways is recruitment of TIRcontaining adaptor proteins, and these adaptor proteins then regulate which intracellular pathway will be activated [27]. Generally, five adaptor proteins have been identified that interact with the TIR domain of TLRs and play a role in the initiation and progression of the TLR signaling pathway. These adaptor proteins are myeloid differentiation factor-88 (MyD88), MyD88 adaptor-like protein (Mal), TIR domain-containing adaptor protein inducing IFNβ (TRIF), TRIF-related adaptor molecule (TRAM), and sterile α- and armadillo-motif-containing protein (SARM) [29, 30]. Based on the adaptor protein used by TLRs, intracellular signaling of TLRs is divided into two pathways: MyD88-dependent signaling pathway which is used by majority of TLRs (except TLR3) and MyD88-independent signaling pathway which is used by TLR3 and TLR4. It is evident that TLR4 is the only TLR that can rely on both pathways [31]. In MyD88-dependent pathway, binding of MyD88 to the receptor is followed by an association between MyD88 and IL receptor-

Initial evidence for the association between insulin resistance and inflammation dates back to more than 100 years ago [33]. Several decades later, it was shown that while administration of proinflammatory cytokine (TNF) to diabetic rats exacerbated their hyperglycemia [34], genetic deletion as well as neutralizing TNF-α was associated with improved insulin sensitivity [35, 36]. These clearly indicated that inflammatory pathways are major contributors in the induction of insulin resistance. Since TLRs play an essential role in the inflammatory pathways, then it would be conceivable to assume that TLRs may participate in the induction of insulin resistance; to date, large numbers of evidences supporting this view have been published [37–40]). As mentioned, TLRs are shown to be expressed in the CNS; therein, they are involved in the physiology and pathophysiology of the CNS. Studies have shown that like peripheral tissues, TLRs (particularly TLR2 and 4) have an important role in the induction of central insulin resistance. It has been shown that central insulin resistance induced by high fat diet (HFD) or obesity and its resulting reduction in neuronal activity and

TLR Members

Mol Neurobiol Fig. 1 Illustration of the different ligands activating TLRs and their resulting MyD88-dependent pathway of TLR signaling. IKK Ik B kinase, IRAK IL receptorassociated kinase, IRF interferon regulatory factors, MAL MyD88 adaptor-like protein, SARM sterile α- and armadillo-motifcontaining protein, TAB TAK1binding protein, TRAF-6 tumor necrosis factor receptorassociated factor-6, TANK TRAFassociated NF-ĸB activator, TBK1 TANK binding kinase, TAK1 transforming growth factor-βactivated protein kinase 1, TRIF TIR domain-containing adaptor protein inducing IFNβ, TRAM TRIF-related adaptor molecule

locomotion could be prevented by genetic deletion of TLR2/4, or neutralizing inflammatory mediators suggesting that TLRinduced neuroinflammatory responses is a causative factor in the induction of central insulin resistance [41, 42]. Consistently, the association between reduction in brain insulin sensitivity and TLR-induced elevation of inflammatory cytokines has also been reported [43, 44]. In addition, genetic deletion of TLR2/4 in mice causes astrocytic insulin actions and markers of glycogen synthesis to be increased, showing that besides neurons, TLRs also affect insulin responsiveness in the astrocytes [42]. Considering these evidences showing that TLRs are main contributors in the induction of brain insulin resistance and the magnificent roles which insulin dysregulation and TLR signaling pathway play in the pathology of different neurological diseases, in the next sections, we will address the current literature about the presence and roles of TLRs in the CNS, and then the possible interactions between insulin and TLR signaling pathways in the initiation and progression of some major pathologies of the CNS will be reviewed.

TLRs in the Brain Expression Accumulating evidences are available indicating that TLRs are expressed in different cellular compartments of the CNS.

In humans, it has been shown that microglia and astrocytes express all functional TLRs (TLR1–9), but other cells express just a number of them. For instance, oligodendrocytes express TLR2 and 3; endothelial cells express TLR2, 4, and 9; and finally, neuronal cells are shown to express TLR2, 3, 4, 8, and 9 [45, 46]. It is noticeable that TLR expression is not constant, and in response to different stimuli like pathogens, cytokines, and environmental stresses, their expression is modulated [28]. TLR Functions in the CNS Besides the important roles of TLRs in the modulation of immune responses within the CNS, these receptors also possess several other functions in the physiology of the CNS. One of these important roles of TLRs is their developmental roles during embryogenesis. It has been shown that neural progenitor cells (NPCs) express TLR2, 3 and 4, and these receptors are implicated in the proliferation as well as differentiation of NPCs. Furthermore, several aspects of adult neuronal physiology such as neurogenesis, neural survival, structural plasticity, and neurite outgrowth are also shown to be modulated by TLRs. As these processes are the main features of the cognitive function of the CNS, it would be conceivable to conclude that TLRs are implicated in cognition and memory. Consistently, several lines of evidences are published showing that members of TLRs contribute in the modulation of

Mol Neurobiol Fig. 2 Illustration of the different ligands activating TLR3 and TLR4 and their resulting MyD88-independent pathway of TLR signaling. See Fig. 1 for abbreviations

TLR4 activation

LPS, HSPs,hyalurnic acid , viral proteins...

dsRNA

TLR activation

TRAM

TRAF-3

TBK1

TRIF

RIP1

TRAF-6 TAB1,2,3

IKK activation

IRF-3 phosphorylation

Type I IFN

p-IRF3

TAK1

I kB degradation

MAPKs phosphorylation

NF-kB

AP1/C-JUN

NF-kB

AP1 C-Jun

Inflammatory cytokines

Nucleus

different types of memory (reviewed in [47]). In addition to the aforementioned physiological functions, TLRs are also involved in the pathogenesis of different neurodegenerative and neurological diseases [47].

interacting signaling pathways which possibly contribute in these pathologies will be discussed in more detail.

Participation of TLRs and Insulin Dysregulation in Brain Pathologies

AD is one the most prevalent neurodegenerative disorders which TLRs and insulin impairment play a role in its pathophysiology. AD is characterized by intercellular neurofibrillary tangles (NFT) and extracellular senile plaques composed of an aggregated form of amyloid beta (Aβ) peptides. These plaques are surrounded by activated microglia and monocytic phagocytes of the brain, and Aβ peptides act as the main stimulator of microglia activation, thereby senile plaques are known as the main foci of local inflammatory responses in AD brains [48]. A number of TLR family members play a pivotal role in Aβ-induced microglia activation, as it has been shown that in microglial cells lacking TLR2 and TLR4, amyloid beta fails to activate P38 and induce cytokine production. In addition, deletion of TLRs in mouse models of AD causes the level of P38 and NF-ĸB to be lower than that of normal AD models [49, 50]. It must be emphasized that activation of

As mentioned, TLRs and impairment of insulin signaling are commonly involved in some important pathological states of the CNS. On the other side, we pointed to literatures which show a positive correlation between TLR activation and development of insulin resistance, and these evidences raise a possibility that adverse effects of neuroinflammation and TLR overactivity in neurodegenerative diseases like AD may be carried out, at least partly, through their deteriorating effects on insulin signaling. In the coming sections, shared involvement of TLRs and insulin dysregulation in the pathology of neurodegenerative diseases like AD and PD as well as neuropsychiatric disorders will be briefly reviewed, and the in the next section, the common

Alzheimer’s Disease

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TLRs by Aβ is not always a harmful pathway, in fact, in early stages of AD, when the Aβ concentration is low, activation of TLRs promotes Aβ clearance by activating microglial uptake [51]. Consistently, it has been demonstrated that Aβ accumulation and memory impairment are increased in mice lacking TLR2 [52]. When the concentration of amyloid beta is high, a situation which can be seen in later stages of AD, TLR activation not only causes detrimental neuroinflammatory pathways to be activated but also microglial mediated phagocytosis of Aβ is inhibited by released cytokines [53–55]. Besides the participation of TLRs in AD, substantive evidences also have been published showing that dysregulation of insulin signaling is associated with the development of AD, and impairment of insulin signaling is known as a key pathological hallmark of AD. This clear involvement of insulin disturbance in AD is so much that AD is alternatively named as “diabetes type 3” (reviewed in [12]). Parkinson’s Disease Parkinson’s disease is another prevalent neurodegenerative disease which TLR activity and insulin dysregulation are commonly involved in its pathophysiology. PD is caused by a progressive loss of dopaminergic neurons of the substantial nigra pars compacta (SNpc) [56]. Release of various proinflammatory cytokines such as IL-1β, TNF-α, interferon-γ, and NO by activated microglial cells of SNpc and its resulting neuroinflammation is believed to play an important role in the neurodegenerative process of this disease [57]. TLRs are the main mediators for triggering of this microglial activation. Accordingly, it has been demonstrated that MPTP administration to TLR4-deficient mice causes less microglial activation when compared with wild-type ones [58]. Furthermore, upregulation of TLRs (TLR3, 4, 7, 9) as well as the key adaptor of TLR signaling (MyD88) was also shown in MPTP-treated mice and postmortem parkinsonian brains [59, 60]. These studies and others clearly indicate that some members of the TLR family are directly involved in the pathology of PD. On the other hand, considerable evidences are available showing that the substantial nigra expresses insulin receptors where insulin protects dopaminergic neurons and plays a role in the regulation of dopamine synthesis, in such a way that insulin disturbances are shown to be associated with the development and progression of PD (reviewed in [12]). Psychiatric Disorders In addition to neurodegenerative diseases, insulin impairment and TLR-brought neuroinflammation are also commonly involved in the pathology of psychiatric disorders. Consistently, it has been shown that injection of inflammatory cytokines (IL-1β, TNF-α) to healthy animals induces behavioral deficits and social withdrawal named as sickness behavior [4].

Meanwhile, involvement of prenatal TLR3 activation in the development of behavioral deficits in adult offspring is also documented [61, 62]. In agreement with these evidences, it was depicted that in blood samples obtained from schizophrenia and bipolar patients, TLR agonists induce higher levels of IL-1β, IL-6, IL-8, and TNF-α release when compared with bloods of healthy people. This observation shows that these disorders are associated with an altered TLR-mediated immune response [63]. Concomitantly, involvement of insulin signaling dysregulation in the pathology of psychiatric disorders is also well documented. Insulin has neuromodulatory effects on important neurotransmitters; furthermore, insulin secretion and insulin receptor sensitivity are shown to be impaired in psychiatric disorders. Additionally, the existence of a positive correlation between diabetes mellitus and behavioral disorders like depression and schizophrenia is also reported by several studies (reviewed in [12]). According to previously mentioned evidences that show an evident overlap between impairment in insulin signaling and TLR activities in some brain pathologies and referring to studies which showed that TLRs participate in the induction of central as well as peripheral insulin resistance, this possibility raises that an interaction between insulin signaling and TLR signaling might be involved in these pathologies. In other words, these studies imply that a bidirectional association between TLRs and insulin signaling pathways may play a role in the development and progression of these disorders. In the following section, we will review the most important pathways where interaction of the two pathways might occur.

Signaling Pathways Involved in the Interaction of Insulin and TLR PI3K/Akt Pathway Phosphatidylinositide 3-kinases (PI3K) is a lipid kinase which plays role in the regulation of different important cellular processes such as cell growth, proliferation, differentiation, motility, survival, and intracellular trafficking. This kinase catalyzes the transfer of the γ-phosphate group of ATP to Dposition of phospho-inositide to form Ptd-Is (3, 4, 5) P3 (PIP3). PIP3 is an upstream activator of Akt (PKB) and a number of other signaling elements [64, 65]. The PI3K/Akt pathway is considered as the major integrator involved in CNS insulin signaling, which takes part in different insulinmediated functions such as neuronal survival and synaptic plasticity [66]. In addition, it has been demonstrated that a common feature in different restorative approaches against neurodegenerative disease models is the activation of the PI3K/Akt pathway [67–69]. Furthermore, disturbance of this pathway is shown to take part in the pathophysiology of psychiatric disorders such as depression, schizophrenia, and

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anxiety [70, 71]. On the other side, the PI3K/Akt pathway is affected by and affects TLR signaling. Despite some controversies about the exact effect of PI3K/Akt on TLR activation, this pathway is generally considered as a negative regulator for TLR signaling pathway. In such a way, TLR activation induces the PI3K/Akt pathway and PI3K/Akt then inhibits TLR activity, and this negative feedback mechanism tends to limit TLR overactivity [65, 72, 73]. This inhibitory effect of the PI3K/Akt pathway on TLR activity is further confirmed when the PI3K/Akt pathway is downregulated, and such situation is associated with TLR-induced inflammatory responses. It has been shown that inhibition of the PI3K/Akt pathway by wortmanin causes TLR-mediated cytokine production to be augmented [74–76]. In accordance with these observations, Bauerfeld et al. have shown that PI3K/Akt is required for recovery from LPS-induced mitochondrial perturbation, and inhibition of this pathway exacerbates LPS damage [77]. Disruption of PI3K/Akt signaling is also shown to be accompanied with increased responsiveness to LPS [78, 79]. These studies raise the possibility that disruption of the PI3K/Akt pathway, as can be seen in situations like insulin resistance, could unbrake TLR activity and this could initiate a deteriorating feedback loop which exacerbates the situations (Fig. 3). GSK3β Glycogen synthase kinase 3β (GSK3β) is a serine-threonine kinase which constitutively is active and is targeted by the PI3K/Akt pathway. One of the most important inhibitors for GSK3β activity is insulin-mediated PI3K/Akt pathway [80]. The importance of insulin-induced suppression of GSK3β is well depicted in studies on diabetic animals, a situation that insulin signaling is impaired and GSK3β is freed from suppression. It has been demonstrated that diabetic GSK3β overactivation plays an essential role in adverse effects associated with diabetes [81]. GSK3β overactivation also plays an important role in the development and progression of insulin resistance, and inhibition of GSK3β is considered as a protective approach against developing insulin resistance [82]. It is evident that existence of a precise balance between GSK3β and insulin activity is a critical issue in normal physiology. In addition to the previously mentioned relation between GSK3β and insulin, substantive evidences are also available showing that GSK3β is an important contributor in the pathology of AD. GSK3β is one of the main kinases responsible for tau hyperphosphorylation, and inhibition of GSK3β is shown to ameliorate tau phosphorylation. Furthermore, GSK3β also takes part in Aβ accumulation as well as learning and memory deficits [83–85]. In such a way, involvement of GSK3β in the pathophysiology of psychiatric disorders like depression and schizophrenia also has been documented [86, 87]. On the other hand, numerous evidences both in the CNS and extraneuronal tissues are also available showing that

GSK3β is an important mediator of TLR-mediated inflammatory responses [88, 89]. In such a way, inhibition of GSK3β ameliorates the adverse effects of inflammation. Consistently, it has been shown that LPS-induced release of cytokines by glial cells is highly dependent on GSK3β activity [90]. The promoting role of GSK3β in neuroinflammatory injuries is further verified by results showing that neuroinflammatory responses could be ameliorated by inhibitors for GSK3β [91]. In addition to participation in the release of inflammatory cytokines, other aspects of the CNS immune system such as tolerance and sensitization are also affected by GSK3β. Consistently, it has been shown that that inhibition of GSK3β is associated with a higher level of tolerance in astrocytes [92]. Besides the role of GSK3β in the TLR4-induced cytokine release, this kinase also takes part in TLR4-mediated apoptosis [93]. IKK/NF-ĸB Pathway IκB kinase/NF-κB (IKK/NF-κB) signaling pathway is the main pathway which takes part in TLR signaling pathway. As mentioned in earlier sections, activation of TLRs by appropriate ligands triggers two MyD88-dependent and MyD88-independent pathways which both result in the activation of the IKK/NF-κB pathway. IKK/NF-κB activation leads to the release of NF-κB and its translocation into the nucleus where NF-κB induces the expression of different cytokine genes such as TNF-α [94, 95]. Several lines of evidences are available showing that activation of this pathway participates in the induction of insulin resistance either directly or indirectly. In following paragraphs, insulin disturbing pathways of IKK/NF-κB will be reviewed briefly. Direct Induction of Insulin Resistance Evidences have been published showing that IKK/NF-κB per se can impair insulin signaling, and this insulin disturbing function is mainly carried out via IKKβ-induced phosphorylation of IRS-1. Accordingly, Gao et al. have shown that activated IKK directly phosphorylates IRS-1 at its serine residue, and chemical inhibition of IKKβ is associated with reduced serine phosphorylation of IRS-1 [94]. In another study, it was demonstrated that mice lacking IKKβ are less susceptible to diet-induced insulin resistance [96]. It has been reported that the direct insulin disturbing role of IKK is done through phosphorylation of ser-307/312 in mouse/human IRS-1 protein, while in an indirect way, phosphorylation of other serine residues is induced by IKKβ [97]. Indirect Induction of Insulin Resistance by IKK/NF-κB PTP1B Protein tyrosine phosphatase 1 B (PTP1B) is a member of the protein tyrosine phosphatase (PTP) family

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Fig. 3 Schematic representation of the signaling pathways linking insulin and TLR signaling. See Fig. 1 for abbreviations

which catalyzes the dephosphorylation of tyrosinephosphorylated proteins. Since then, PTP1B is considered as a negative regulator for insulin signaling [98]. It has been reported that PTP1B takes part in the development of insulin resistance both in neuronal and non-neuronal tissues [99, 100]. Consistently, mice lacking PTP1B are shown to be more insulin sensitive [101]. Moreover, inhibition of neuronal PTP1B is shown to be accompanied with improved insulin signaling, an observation which fortifies the role of PTP1B in neuronal insulin resistance [102].

PTP1B is one of the mediators employed by the IKK/ NF-κB pathway to induce insulin resistance [103]. In vivo and in vitro evidences have shown that inflammation and proinflammatory cytokines are involved in the regulation of PTP1B. For example, in an experiment done on hypothalamic organotypic culture, it was demonstrated that TNF-α, as a transcriptional target as well as activator of the IKK/NF-κB pathway, increased the expression of PTP1B [104]. Similar results were also obtained from an in vivo experiment [105]. These effects of TNF-α are at least partly carried out via the IKK/NF-κB pathway [104, 105]. Consistent with this

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hypothesis, it has been shown that activation of NF-κB in the hypothalamus and its subsequent expression of PTP1B interfere with hypothalamus insulin signaling [103]. Interestingly, evidences are also available indicating that brain PTP1B activity is also linked with major neurodegenerative diseases. Accordingly, Mody et al. have shown that in genetic models of AD, the neuronal level of PTP1B is increased and these animals were reported to be more susceptible to dietinduced insulin resistance [106]. Additionally, it has been demonstrated that PTP1B has a regulatory role in tyrosine phosphorylation of α-synuclein, and inhibition of this phosphatase was shown to prevent cell death of dopaminergic neurons, in such a way that inhibition of PTP1B in animal models of PD was also demonstrated to improve their behavioral deficits [107]. Based on these reports showing a clear involvement of PTP1B in the development of insulin resistance and its role in neurodegenerative diseases in addition to activating the effects of the IKK/NF-κB pathway on this phosphatase, a possibility is raised that PTP1B could be a point of interaction between insulin resistance and TLR-induced neuroinflammatory responses in brain pathologies. S6K1 Another signaling element employed by IKKβ to induce insulin resistance is S6K1 (p70S6K) [97]. S6K1 is a downstream of the PI3K/Akt/mTOR pathway which participates in the growth-promoting functions of insulin signaling. Besides that, S6K1 also plays an inhibitory role in insulin signaling pathway. As when S6K1 is activated by insulin, it phosphorylates IRS-1 on serine residues causing insulin signaling to be inhibited. This way provides a negative feedback mechanism to control insulin actions [97, 108]. This S6K1mediated phosphorylation of IRS-1 is another way which inflammatory pathways employ to induce insulin resistance. Consistently, it has been shown that TNF-α could activate S6K1 in an Akt-independent but IKKβ-dependent manner, thereby TNF-α-mediated activation of S6K1 induces insulin resistance via a mechanism that requires IKKβ [97]. So it seems that S6K1 is another possible point of interaction between insulin and TLR-induced inflammatory responses. In such a way, activation of TLR-induced activation of the IKK/NF-κB pathway and its resulting release of TNF-α can fortify the negative feedback loop in insulin signaling, and by this way, TLR activation may take part in insulin disturbances seen in brain disorders. MAPK Mitogen-activated protein kinases pathway (MAPKs) are a group of serine-threonine kinases playing roles in a variety of cellular activities and are divided into three main subgroups which are as follows: extracellular signal-regulated kinases (ERKs), Jun N-terminal kinases (JNKs), and P38 MAPK [109]. As mentioned in earlier sections, MAPKs are another

important signaling pathway which participates in TLRinduced inflammatory responses [45]. It has been shown that inhibition of MEK1/2, p38, or JNK causes the LPS or flagellininduced overexpression of proinflammatory cytokines (IL-1β, NO) to be inhibited [110]. In another study, Johnsen et al. have shown that P38 is required for TLR-3-induced expression of interferon-β [111]. It is believed that the type of agonists and their sensing TLRs determine the relative importance of each P38, JNK, or ERK in the TLR signaling pathway [110]. For instance, while JNK, P38, and ERK play equal roles in TLR4induced responses, in TLR5-mediated response, JNK plays the dominant role and TLR7-mediated gene regulation is more dependent on P38 [110]. Besides participation in cellular response to stress stimuli like TLR activation, MAPK members also play a significant role in the induction of insulin resistance as much as some believe that JNK is the central mediator in the development of insulin resistance [112]. Consistently, it has been shown that inhibition of central JNK increases the hypothalamic insulin sensitivity [113]. JNK-induced development of insulin resistance is carried out via phosphorylation of serine residues of IRS [114, 115]. In such a way, another member of MAPKs, ERK, also participates in the impairment of insulin signaling, and inhibition of ERK activation by MEK inhibitor is reported to prevent TNF-α-induced development of insulin resistance [116]. Two mechanisms for ERK-induced insulin resistance are reported: IRS-1 phosphorylation and negative regulation of IRS-1 expression [117]. These reports about the harmful effects of ERK are in contrast to the traditional view about the survival effects of this kinase; it has been shown that however transient activation of ERK serves to be neuroprotective but sustained activation of this kinase contributes in neuronal death, indicating that duration of ERK activity is a determining factor in ERK activity [118–120]. Besides JNK and ERK evidences are also available showing that P38 also participates in the induction of insulin resistance, as it has been depicted that TNF-α-induced insulin resistance in vascular cells is carried out via the P38 pathway [121]. Besides these evidences about the participation of MAPKs in insulin resistance, numerous reports have been published which indicate that MAPKs also play important roles in the pathology of neurodegenerative as well as psychiatric disorders. For instance, it have been demonstrated that activated forms of JNK, P38, and ERK are increased in the susceptible neurons of AD patients [122]. Furthermore, involvement of these MAPKs in different aspects of AD, like tau hyperphosphorylation [123, 124], Aβ accumulation [125, 126], and Aβ-induced apoptosis [127], is also documented. Similarly, participation of MAPK activity in the pathology of Parkinson’s disease [128], anxiety, depression [129], and schizophrenia [130] also has been demonstrated. Collectively, these evidences lead us to assume that activation of MAPK members in brain pathologies may be involved in the interaction of TLRs and insulin signaling pathway.

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SOCS-3 Suppressor of cytokine signaling-3 (SOCS-3) is a member of a larger family of SOCS proteins which are activated by a variety of cytokines and TLRs, and then they inhibit the same signaling pathways that lead to their induction. In this way, they provide a negative feedback mechanism for inflammatory responses [131]. Besides the regulatory role of SOCS-3 proteins for cytokine signaling, this protein is also involved in the induction of insulin resistance, and the SOCS-3-mediated insulin disturbance is achieved via targeting of IRS-1 and IRS-2 for proteosomal degradation [132]. Consistently, it has been shown that insulin-induced phosphorylation of insulin receptor, IRS and Akt are diminished by overexpression of SOCS-3 [133]. In addition, SOCS-3 is also shown to take part in the induction of neuronal insulin resistance, as it has been shown that sensitivity to insulin is increased in neural cells with conditional knockout of SOCS-3 [134]. Collectively, it seems that SOCS-3 plays a dual role during inflammatory responses. On one hand, its suppressor function on inflammatory responses could protect cells against the adverse effects of inflammation. On the other hand, activation of SOCS-3 by TLRs and cytokines could impair insulin signaling. These results imply that SOCS-3 could be considered as another hypothetical point which TLRs could interact with insulin signaling and promote the common pathologies of the CNS.

Concluding Remarks After several years of arduous work, showing a clear involvement of insulin signaling in the physiology and pathophysiology of CNS, elucidating the possible ways which ends in disruption of insulin functions seems to be essential. In the present work, we focused on the role of TLR activity and its resulting neuroinflammation in the pathologies of the CNS which are associated with insulin signaling disruption, and the possible signaling points which could link insulin and TLR signaling were reviewed. This could open a way to start more specific researches to find the exact and relative participation of these proposed ways in each condition. Conflict of Interest The authors declare that they have no conflict of interests.

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