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Toll-like receptor downstream signaling

Toll-like receptor downstream signaling The family of Toll-like receptors (TLRs) senses conserved structures found in a broad range of pathogens, causing innate immune responses that include the production of inflammatory cytokines, chemokines and interferons. The signal transduction is initiated from the Toll/interleukin-1 receptor (TIR) domain of TLRs after pathogen recognition. Almost all TLRs use a TIR-containing adapter MyD88 to activate a common signaling pathway that results in the activation of NF-κB to express cytokine genes relevant to inflammation. Recently, three further TIR-containing adapters have been identified and shown to selectively interact with several TLRs. In particular, activation of the TRIF-dependent pathway confers antiviral responses by inducing anti-viral genes including that encoding interferon-β. Taken together, these results indicate that the interaction between individual TLRs and the different combinations of adapters directs appropriate responses against distinct pathogens. Keywords: inflammatory cytokines, innate immunity, interferons, TIR-domain containing adapter, TLR Introduction major domains characterized by leucine-rich repeats (LRR In Drosophila, Toll was initially identified as an essential domain) and Toll/interleukin-1 receptor (TIR domain) protein for the determination of dorsoventral polarity domain (Fig. 1). The first evidence of TLRs in the during early embryogenesis. Subsequently, it was shown recognition of pathogens was reported from studies with that flies with a mutant Toll gene are highly susceptible to mice carrying a point-mutated or disrupted Tlr4 gene fungal infection because of a defective production of [3,4]. These mice are unresponsive to bacterial specific anti-fungi peptides upon infection, demonstrating lipopolysaccharide (LPS), an integral component of the that Toll is a receptor that detects fungi invasion to trigger outer membranes of Gram-negative bacteria that can immune responses [1]. In 1997, a human gene similar to cause endotoxin shock. Subsequently, the generation of the Toll gene was identified through the bioinformatic knockout mice for each TLR gene has revealed respective approach [2]. Initial study demonstrated that this gene pathogens that can be recognized by each TLR. TLR2 is product can promote the expression of genes encoding involved in the responses to a variety of bacterial inflammatory cytokines, suggesting that Toll in mammals components that include peptidoglycan, lipoproteins/ also has a function in innate immune responses. A further lipopeptides, glycosyl-phosphatidylinositol anchors from five genes homologous to the Toll gene were Trypanosoma cruzi, and zymosan [5–7]. However, subsequently identified, and these genes were referred to recognition of these TLR2 ligands requires another TLR as the Toll-like receptor (TLR) family. So far, 11 members family member. The mycoplasmal diacylated lipopeptide of the TLR family (TLR1–TLR11) have been identified. In MALP-2 is recognized by a heterodimer of TLR2 and both Drosophila and humans, Toll/TLRs consists of two TLR6, whereas the bacterial triacylated lipopeptide AP-1 = activator protein-1; DCs = dendritic cells; dsRNA = double-stranded RNA; GARG16 = glucocorticoid-attenuated response gene 16; IFN = interferon; IKK = IκB kinase; IL-1R = interleukin-1 receptor; IP = interferon-inducible protein; IRAK = interleukin-1 receptor-associated kinase; IRF = interferon regulatory factor; IRG-1 = immune response gene 1; LPS = lipopolysaccharide; LRR = leucine-rich repeats; MAL = MyD88-like adaptor; MALP-2 = macrophage-activating lipopeptide-2; MAP = mitogen-activated protein; MyD88 = myeloid differentiation factor 88; NF-κB = nuclear factor kappa B; RHIM = RIP homotypic interaction motif; RIP = receptor-interacting protein; TIR = Toll/interleukin-1 receptor; TLR = Toll-like receptor; 12 TRAF = TNF receptor associated factor; TRAM = TRIF-related adaptor molecule; TRIF = TIR-domain-containing adaptor-inducing interferon beta. Available online http://arthritis-research.com/content/7/1/12 Figure 1 Structure and ligands for Toll-like receptors (TLRs). dsRNA, double-stranded RNA; LPS, lipopolysaccharide; TIR, Toll/interleukin-1 receptor. PAM3CSK4 is recognized by a heterodimer of TLR2 and Signal transduction pathway of interleukin-1 TLR1 [8,9]. Flagellin, a 55 kDa monomer obtained from receptor (IL-1R) and TLRs bacterial flagellum, the polymeric rod-like appendage TLRs signal through a pathway conserved in the IL-1R extending from the outer membrane of Gram-negative family [17]. The TIR domain, which is present in all TLRs bacteria, is also a potent pro-inflammatory inducer, which and IL-1R family members, is responsible for initiating a is recognized by TLR5 [10]. TLR3 recognizes double- signaling cascade through homophilic or heterophilic stranded (ds) RNA that is generated in the lifecycle of interactions with TIR-domain-containing adapters. Almost RNA viruses during infection [11]. TLR7 recognizes the all TLRs and IL-1Rs recruit a TIR-domain-containing pharmaceutical compounds imiquimod (also known as adapter protein MyD88. Upon association with TLRs or IL- Aldara, R-837 or S-26308) and resiquimod (also known 1Rs, MyD88 in turn recruits members of IL-1R-associated as R-848 or S-28463) [12]. These compounds of the kinase (IRAK) family through interactions between the imidazoquinoline family are known to have potent antiviral death domains. Once phosphorylated, IRAK1 and IRAK4 and antitumor activities. TLR7 and its close relative TLR8 dissociate from the receptor complex and then associate also recognize the single-stranded RNA present in with TRAF6, a member of the TRAF family. In contrast, numerous viruses [13,14]. TLR9 recognizes unmethylated IRAK-M, which lacks the kinase activity, has been shown 2′-deoxyribo(cytidine-phosphate-guanosine) (CpG) DNA to prevent dissociation of IRAK1 and IRAK4 from receptor motifs commonly present in bacterial and viral genomes complex, thereby negatively regulating the TLR signaling that have immunostimulatory activities [15]. It has recently [18,19]. Activated TRAF6 can form a complex with the been shown that TLR11, which is abundant in the kidney ubiquitin-conjugating enzymes Ubc13 and Uev1A; TRAF6 and bladder, senses uropathogenic bacteria [16] (Fig. 1). then acts as the ubiquitin E3 ligase to activate the kinase 13 Arthritis Research & Therapy Vol 7 No 1 Kawai and Akira TAK1, a member of the mitogen-activated protein (MAP) Figure 2 kinase kinase kinase family [20,21]. TAK1 is thought to activate two divergent pathways that lead to the transcription factors NF-κB and AP-1 through kinase cascades involving the canonical IκB kinase complex (IKK- α, IKK-β, and IKK-γ) and MAP kinases (ERK, JNK, p38), respectively, to induce the expression of target genes. However, there is no evidence showing that TAK1 is really involved in these pathways in vivo. TIR-domain containing adapters MyD88 MyD88 was originally identified as one of the myeloid Structure of Toll/interleukin-1 receptor (TIR)-containing adapter differentiation primary response genes rapidly induced by proteins. DD, death domain. IL-6 in M1 myeloleukemic cells. MyD88 contains two domains characterized by a death domain and a TIR domain, but lacks a putative transmembrane region, suggesting that MyD88 might function as an adapter more alternative pathways leading to the expression of protein in cytoplasm (Fig. 2). Consequently, MyD88 was certain genes associated with the delayed activation of shown to be recruited to the IL-1R after IL-1 ligation and NF-κB and AP-1 probably exist in TLR4 signaling. In this to associate with IRAK1, resulting in the activation of regard, genes induced by LPS in a MyD88-independent transcription factors NF-κB and AP-1 [22–24]. Studies on manner were sought by subtractive screening, which MyD88-deficient mice clearly demonstrated that MyD88 is revealed that several genes were considerably induced an essential component in the responses to IL-1 and the after stimulation with LPS in MyD88-deficient cells [29]. IL-1-related cytokine IL-18 [25]. All of the responses to IL- These include interferon-inducible protein (IP)-10, a 1 and IL-18 and the activation of NF-κB and MAP kinases member of the CXC chemokines, glucocorticoid- were completely defective in cells from MyD88-deficient attenuated response gene 16 (GARG16) and immune- mice. Subsequent investigation confirmed that MyD88 is responsive gene 1 (IRG-1), all of which are so-called IFN- also used in TLR signaling. In MyD88-deficient mice, the inducible genes. Northern blot analyses showed that production of inflammatory cytokines such as tumor induction of these genes by LPS is comparable between necrosis factor-α, IL-1β and IL-6, the proliferation of B wild-type and MyD88-deficient macrophages, but is cells, and the induction of endotoxin shock in response to completely abolished in TLR4-deficient cells. Thus, there LPS (TLR4 ligand) are also completely abolished, is a MyD88-independent pathway that mediates the demonstrating that MyD88 is indispensable for the induction of IFN-inducible genes in TLR4 signaling [29]. responses to LPS in vivo [26]. In addition, cells from MyD88-deficient mice are totally unresponsive to peptido- The induction of some IFN-inducible genes is thought to glycan, lipoprotein, CpG DNA, and imidazoquinolines in be regulated in part by the transcription factor IRF3, a terms of cytokine production [12,27,28] (Fig. 3). member of the interferon regulatory factor (IRF) family. IRF3 is normally present in cytoplasm. Upon stimulation, In addition to inflammatory responses mediated by the IRF3 is phosphorylated at multiple serine residues to form MyD88-dependent pathway, a subset of TLRs can also a homodimer, moving to the nucleus, where it regulates induce appropriate responses depending on the types of the expression of IFN-β or other target genes [30]. IRF3- pathogens. In TLR4-deficient macrophages, all of the deficient mice are defective in the LPS-mediated induction responses to LPS tested are completely abolished, and of IFN-β and IFN-inducible genes but are intact in the the LPS-induced activation of NF-κB and MAP kinases production of inflammatory cytokines [31]. Furthermore, fails totally, indicating that TLR4 is an essential signaling the induction of some of IFN-inducible genes is regulated receptor for LPS [4,26]. In MyD88-deficient cells, the in part secondarily to LPS-inducible IFN-β, which binds to production of inflammatory cytokines and the activation of the IFN-α/β receptor and activates the classical IRAK1 in response to LPS are also diminished. However, JAK–STAT pathway [32,33]. These results suggest that NF-κB and MAP kinases are unexpectedly activated after IRF3 is responsible for the MyD88-independent induction stimulation with LPS in MyD88-deficient cells, but the of IFN-inducible genes. Indeed, IRF3 is normally activated activation was delayed in comparison with that in wild-type in response to LPS in MyD88-deficient cells [29,34]. cells [26]. In contrast, the activation of NF-κB and AP-1 in Thus, TLR4 is capable of inducing two different pathways, response to other stimuli such as ligands of TLR2, TLR5, namely the MyD88-dependent pathway responsible for TLR7, and TLR9 was completely defective in MyD88- the induction of a core set of inflammatory cytokines and 14 deficient cells. These aspects strongly suggest that one or the MyD88-independent pathway leading to the activation Available online http://arthritis-research.com/content/7/1/12 Figure 3 Schematic representation of Toll-like receptor (TLR) signaling pathways. All TLRs except for TLR3 are thought to share the MyD88-dependent pathway that activates NF-κB and mitogen-activated protein (MAP) kinases, leading to the induction of inflammatory cytokine genes. Interleukin-1 receptor-associated kinases (IRAKs) and TRAF6 are located downstream of MyD88. TIRAP is involved in the MyD88-dependent pathway downstream of TLR2 and TLR4. TRIF is utilized in the TLR3-mediated and TLR4-mediated activation of interferon regulatory factor (IRF)3 and the subsequent induction of IRF3-dependent gene expression such as interferon-β (IFN-β). TRAM is specifically involved in the activation of IRF3 in TLR4 signaling. The complex of TBK1/IκB kinase-i (IKK-i) is responsible for the activation of IRF3 downstream of TRIF in TLR3 and TLR4 signaling. TRAF6 is also involved in the TRIF-dependent activation of NF-κB and MAP kinases. Receptor-interacting protein (RIP) mediates TRIF-dependent NF-κB activation. DD, death domain. of IRF3 and IFN-β production (Fig. 3). In addition, TIRAP (MAL) stimulation with LPS also augments the surface The finding that a MyD88-independent pathway exists in expression of co-stimulatory molecules such as CD40, TLR4 signaling suggests that another protein, presumably CD80 and CD86 to induce the maturation of dendritic containing the TIR domain, acts downstream of TLR4 to cells (DCs) in MyD88-deficient mice, indicating that the activate IRF3 independently of MyD88. In this model, a maturation of DCs also proceeds without the MyD88- second TIR-domain-containing adapter TIRAP (also dependent pathway [35]. known as MAL) was identified by means of a database search, on the basis of the similarity to the TIR domain The MyD88-independent pathway is also used in TLR3 (Fig. 2) [36,37]. Expression of dominant-negative TIRAP, signaling. dsRNA (TLR3 ligand) also activates IRF3 and which encodes only the TIR domain, blocked NF-κB induces the expression of IFN-inducible genes, and these activation by TLR4 but not that by TLR9, and cell- inductions are normal in MyD88-deficient cells [34]. permeable peptide-mediated inhibition of TIRAP function Furthermore, the induction of IFN-inducible genes and the also decreased the induction of IP-10 by TLR4. Thus, activation of IRF3 are not observed after stimulation of TIRAP was expected to participate specifically in the macrophages with TLR2 ligands, showing the specific use TLR4-mediated MyD88-independent pathway. However, of the MyD88-independent pathway in TLR3 and TLR4 TIRAP-deficient mice were unexpectedly impaired in the signaling [29]. activation of NF-κB and MAP kinases and in the 15 Arthritis Research & Therapy Vol 7 No 1 Kawai and Akira production of inflammatory cytokines induced by TLR1, Downstream events of TRIF-dependent activation of NF- TLR2, TLR6, and TLR4 ligands [38,39]. In contrast, the κB are still unclear. It has recently been reported that TRIF TLR4-mediated maturation of DCs and the activation of associates directly with TRAF6 [44]. Three TRAF-binding IRF3 were intact in TIRAP-deficient mice. Taken together, motifs are present in the amino-terminal region of TRIF, these results indicate that TIRAP is unlikely to mediate the and a mutagenesis study demonstrated that these motifs MyD88-independent pathway; rather, it participates in the are necessary for association with TRAF6. Disruption of MyD88-dependent pathway downstream of TLR2 and TRAF-binding motifs in TRIF resulted in reduced activation TLR4 (Fig. 3). of NF-κB. Given that TRAF6 activates NF-κB but not the IFN-β promoter, TRIF activates NF-κB by recruitment of TRIF (TICAM1) TRAF6 via the TRAF-binding motifs [44]. In addition to A third TIR-domain containing the adapter TRIF (also amino-terminal TRAF-binding motifs, NF-κB is also known as TICAM1) was independently identified by the activated from the carboxy-terminal domain of TRIF, which database search and as an interacting partner with TLR3 lacks the TIR domain [40]. It has recently been reported by yeast two-hybrid screening (Fig. 2) [40,41]. Initial that the kinases receptor-interacting protein (RIP)-1 and studies indicated that the overexpression of TRIF strongly RIP3 are recruited to TRIF through the RIP homotypic activates the IFN-β-dependent promoter, in contrast to interaction motif (RHIM) found in the carboxy-terminal the lack of MyD88-mediated or TIRAP-mediated region of TRIF [45]. In cells deficient for the Rip1 gene, activation of the IFN-β-dependent promoter. TRIF, as well TLR3-mediated activation of NF-κB was selectively as MyD88 and TIRAP, also activates NF-κB after impaired, whereas activation of JNK or IFN-β promoter overexpression. Moreover, the expression of dominant- was intact, indicating that TLR3 uses RIP1 for activation of negative TRIF or the siRNA-mediated reduction of TRIF NF-κB downstream of TRIF; this was in contrast to other expression blocked TLR3-dependent activation of IRF3. TLRs, which use IRAKs for the activation of NF-κB (Fig. 3). These findings suggested that TRIF is involved in the MyD88-independent pathway. Subsequent generations TRAM (TICAM2, TIRP) of TRIF-deficient mice clearly revealed that they were The fourth TIR-domain-containing adapter was severely impaired in the induction of IFN-β and IFN- independently identified in the database search and termed inducible genes mediated by TLR3 and TLR4 ligands TRAM, TIRP, or TICAM2 (Fig. 2) [41,46,47]. It has recently [42]. Furthermore, activation of IRF3 was not observed in been demonstrated that responses of TRAM-deficient mice TRIF-deficient cells. Analyses of mutant mice designated to TLR2, TLR7, and TLR9 ligands are intact in terms of lps2, which were generated by N-ethyl-N-nitrosourea- production of inflammatory cytokines [48]. However, the induced random mutations, have also revealed that TRIF LPS (TLR4 ligand)-induced production of inflammatory is an lps2 gene product that is essential for responses cytokines was specifically impaired in TRAM-deficient mediated by TLR3 and TLR4 [43]. Thus, TRIF is a critical mice. Moreover, the induction of IFN-β and activation of protein that mediates the MyD88-independent pathway in IRF3 in response to LPS was severely impaired in TRAM- TLR3 and TLR4 signaling (Fig. 3). Furthermore, it is deficient mice, indicating that TRAM is also involved in the noteworthy that the production of inflammatory cytokines MyD88-independent pathway. These responses in TRAM- induced by LPS was severely impaired in both TRIF- deficient mice are very similar to those found in TRIF- deficient mice and MyD88-deficient mice. However, LPS- deficient mice, except for TLR3, to which TRAM-deficient induced activation of IRAK1 and early-phase activation of mice are normally responsive. Thus, TRAM specifically NF-κB and MAP kinases was normally found in TRIF- mediates the MyD88-independent pathway in TLR4 deficient cells; this is in contrast to MyD88-deficient cells, signaling but not in TLR3 signaling (Fig. 3). which show impaired activation of IRAK1 and late-phase activation of NF-κB and MAP kinases [29,42]. These Non-canonical IKKs findings strongly suggest that both the MyD88- The canonical IKKs (IKK-α and IKK-β) are required for the dependent and MyD88-independent pathways are activation of NF-κB mediated by TLRs and IL-1R [17]. required for the induction of genes for inflammatory These IKKs phosphorylate NF-κB inhibitor IκBs, leading to cyokines, whereas activation of the MyD88-independent the ubiquitination and degradation of IκBs by the (TRIF-dependent) pathway is sufficient to induce IRF3- proteasome pathway. NF-κB in turn translocates into the dependent IFN-β and IFN-inducible genes. In contrast, nucleus, where it induces the expression of target genes. activation of the MyD88-dependent pathway is sufficient Two kinases related to the canonical IKKs, TBK1 (also for the induction of inflammatory cytokines in the case of known as NAK and T2K) and IKK-i (also known as IKK-ε), TLR2, TLR5, TLR7, TLR9, and IL-1R. Thus, only TLR4 were identified [49,50]. These ‘non-canonical’ IKKs were uses both the MyD88-dependent and MyD88- also implicated in NF-κB activation, although the precise independent pathways for the induction of inflammatory mechanism is unclear. It has recently been shown that cytokines, although it remains unclear why both pathways forced expression of either TBK1 or IKK-i strongly 16 are necessary. enhances IFN-β-promoter-dependent reporter gene Available online http://arthritis-research.com/content/7/1/12 expression [51,52]. Furthermore, the kinase activities are these TLRs probably share the same signaling pathway. required for IFN-β-promoter activation, suggesting that Although there is still a need to characterize a specific TBK1/IKK-i activates IFN-β promoter by phosphorylating pathway that each TLR uses, understanding such one or more appropriate substrates. Indeed, TBK1/IKK-i is pathways will be therapeutically useful in the control of shown to be capable of phosphorylating the serine inflammatory and anti-viral responses. residues that are critical for activating IRF3 in vitro [51,52]. In cells deficient for the Tbk1 gene, the dsRNA- Roles of TLRs in the pathogenesis of rheumatoid arthritis mediated or LPS-mediated activation of IRF3 (dimer have been investigated. It was demonstrated that formation, nuclear localization) and induction of IRF3- peptidoglycan and bacterial DNA, which is recognized by dependent genes such as IFN-β, GARG16 and IP-10 TLR2 and TLR9, could be detected in the synovium of were considerably reduced, whereas the induction of patients with rheumatoid arthritis [58]. Furthermore, inflammatory cytokines, which is regulated by the MyD88- synovial cells express low levels of TLR2 and TLR9, and dependent pathway and activation of NF-κB and MAP TLR2 is upregulated by exposure to peptidoglycan [59,60]. kinases, was not impaired [53]. Thus, TBK1 is specifically In addition, TLRs have been shown to recognize involved in the induction of IRF3-dependent genes endogenous ligands present in tissues and cells in the mediated by TLR3 and TLR4 (Fig. 3). In contrast, IKK-i- absence of bacterial infection. TLR2 activates cells through deficient cells normally respond to LPS and dsRNA to the recognition of heat shock protein 70 and necrotic cells, induce both IRF3-dependent and NF-κB-dependent gene both of which are detected in synovial tissue of patients expression. However, in TBK1/IKK-i doubly deficient cells with rheumatoid arthritis [61]. These findings suggest that the residual induction of IFN-inducible genes found in TLRs contribute to the pathogenesis of rheumatoid TBK1-deficient cells was completely abolished, indicating arthritis, and targeting the TLR signaling pathway will raise that IKK-i also participates in the pathway dependent on the possibility of a drug discovery to control inflammation TLR3 and TLR4 [54]. It has recently been reported that induced in patients with rheumatoid arthritis. TRIF also binds TBK1 through the amino-terminal region which shares the binding with TRAF6, and the association Competing interests between TRIF and TBK1 seems to require the kinase The author(s) declare that they have no competing interests. activity of TBK1 [44]. Furthermore, expression of the kinase-negative mutant of TBK1 significantly blocked Acknowledgements We thank members of the Akira laboratory for helpful discussions, and TRIF-dependent activation of the IFN-β promoter, thus M. Hashimoto for her excellent secretarial assistance. indicating that TBK1 and IKK-i act downstream of TRIF. TBK1 and IKK-i also bind TANK (also known as I-TRAF) References and a newly identified TANK-related protein NAP1 1. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA: The dorsoventral regulatory gene cassette spatzle/Toll/cactus [49,55,56]. 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Schett G, Redlich K, Xu Q, Bizan P, Groger M, Tohidast-Akrad M, Kiener H, Smolen J, Steiner G: Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) acti- vation in rheumatoid arthritis synovial tissue: differential reg- ulation of hsp70 expression and HSF1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and anti-inflammatory drugs. J Clin Invest 1998, 102:302-311. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arthritis Research & Therapy Springer Journals

Toll-like receptor downstream signaling

Kawai, Taro; Akira, Shizuo
Arthritis Research & Therapy , Volume 7 (1): 8 – Nov 1, 2004
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Springer Journals
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2004 BioMed Central Ltd
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1478-6354
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10.1186/ar1469
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Abstract

The family of Toll-like receptors (TLRs) senses conserved structures found in a broad range of pathogens, causing innate immune responses that include the production of inflammatory cytokines, chemokines and interferons. The signal transduction is initiated from the Toll/interleukin-1 receptor (TIR) domain of TLRs after pathogen recognition. Almost all TLRs use a TIR-containing adapter MyD88 to activate a common signaling pathway that results in the activation of NF-κB to express cytokine genes relevant to inflammation. Recently, three further TIR-containing adapters have been identified and shown to selectively interact with several TLRs. In particular, activation of the TRIF-dependent pathway confers antiviral responses by inducing anti-viral genes including that encoding interferon-β. Taken together, these results indicate that the interaction between individual TLRs and the different combinations of adapters directs appropriate responses against distinct pathogens. Keywords: inflammatory cytokines, innate immunity, interferons, TIR-domain containing adapter, TLR Introduction major domains characterized by leucine-rich repeats (LRR In Drosophila, Toll was initially identified as an essential domain) and Toll/interleukin-1 receptor (TIR domain) protein for the determination of dorsoventral polarity domain (Fig. 1). The first evidence of TLRs in the during early embryogenesis. Subsequently, it was shown recognition of pathogens was reported from studies with that flies with a mutant Toll gene are highly susceptible to mice carrying a point-mutated or disrupted Tlr4 gene fungal infection because of a defective production of [3,4]. These mice are unresponsive to bacterial specific anti-fungi peptides upon infection, demonstrating lipopolysaccharide (LPS), an integral component of the that Toll is a receptor that detects fungi invasion to trigger outer membranes of Gram-negative bacteria that can immune responses [1]. In 1997, a human gene similar to cause endotoxin shock. Subsequently, the generation of the Toll gene was identified through the bioinformatic knockout mice for each TLR gene has revealed respective approach [2]. Initial study demonstrated that this gene pathogens that can be recognized by each TLR. TLR2 is product can promote the expression of genes encoding involved in the responses to a variety of bacterial inflammatory cytokines, suggesting that Toll in mammals components that include peptidoglycan, lipoproteins/ also has a function in innate immune responses. A further lipopeptides, glycosyl-phosphatidylinositol anchors from five genes homologous to the Toll gene were Trypanosoma cruzi, and zymosan [5–7]. However, subsequently identified, and these genes were referred to recognition of these TLR2 ligands requires another TLR as the Toll-like receptor (TLR) family. So far, 11 members family member. The mycoplasmal diacylated lipopeptide of the TLR family (TLR1–TLR11) have been identified. In MALP-2 is recognized by a heterodimer of TLR2 and both Drosophila and humans, Toll/TLRs consists of two TLR6, whereas the bacterial triacylated lipopeptide AP-1 = activator protein-1; DCs = dendritic cells; dsRNA = double-stranded RNA; GARG16 = glucocorticoid-attenuated response gene 16; IFN = interferon; IKK = IκB kinase; IL-1R = interleukin-1 receptor; IP = interferon-inducible protein; IRAK = interleukin-1 receptor-associated kinase; IRF = interferon regulatory factor; IRG-1 = immune response gene 1; LPS = lipopolysaccharide; LRR = leucine-rich repeats; MAL = MyD88-like adaptor; MALP-2 = macrophage-activating lipopeptide-2; MAP = mitogen-activated protein; MyD88 = myeloid differentiation factor 88; NF-κB = nuclear factor kappa B; RHIM = RIP homotypic interaction motif; RIP = receptor-interacting protein; TIR = Toll/interleukin-1 receptor; TLR = Toll-like receptor; 12 TRAF = TNF receptor associated factor; TRAM = TRIF-related adaptor molecule; TRIF = TIR-domain-containing adaptor-inducing interferon beta. Available online http://arthritis-research.com/content/7/1/12 Figure 1 Structure and ligands for Toll-like receptors (TLRs). dsRNA, double-stranded RNA; LPS, lipopolysaccharide; TIR, Toll/interleukin-1 receptor. PAM3CSK4 is recognized by a heterodimer of TLR2 and Signal transduction pathway of interleukin-1 TLR1 [8,9]. Flagellin, a 55 kDa monomer obtained from receptor (IL-1R) and TLRs bacterial flagellum, the polymeric rod-like appendage TLRs signal through a pathway conserved in the IL-1R extending from the outer membrane of Gram-negative family [17]. The TIR domain, which is present in all TLRs bacteria, is also a potent pro-inflammatory inducer, which and IL-1R family members, is responsible for initiating a is recognized by TLR5 [10]. TLR3 recognizes double- signaling cascade through homophilic or heterophilic stranded (ds) RNA that is generated in the lifecycle of interactions with TIR-domain-containing adapters. Almost RNA viruses during infection [11]. TLR7 recognizes the all TLRs and IL-1Rs recruit a TIR-domain-containing pharmaceutical compounds imiquimod (also known as adapter protein MyD88. Upon association with TLRs or IL- Aldara, R-837 or S-26308) and resiquimod (also known 1Rs, MyD88 in turn recruits members of IL-1R-associated as R-848 or S-28463) [12]. These compounds of the kinase (IRAK) family through interactions between the imidazoquinoline family are known to have potent antiviral death domains. Once phosphorylated, IRAK1 and IRAK4 and antitumor activities. TLR7 and its close relative TLR8 dissociate from the receptor complex and then associate also recognize the single-stranded RNA present in with TRAF6, a member of the TRAF family. In contrast, numerous viruses [13,14]. TLR9 recognizes unmethylated IRAK-M, which lacks the kinase activity, has been shown 2′-deoxyribo(cytidine-phosphate-guanosine) (CpG) DNA to prevent dissociation of IRAK1 and IRAK4 from receptor motifs commonly present in bacterial and viral genomes complex, thereby negatively regulating the TLR signaling that have immunostimulatory activities [15]. It has recently [18,19]. Activated TRAF6 can form a complex with the been shown that TLR11, which is abundant in the kidney ubiquitin-conjugating enzymes Ubc13 and Uev1A; TRAF6 and bladder, senses uropathogenic bacteria [16] (Fig. 1). then acts as the ubiquitin E3 ligase to activate the kinase 13 Arthritis Research & Therapy Vol 7 No 1 Kawai and Akira TAK1, a member of the mitogen-activated protein (MAP) Figure 2 kinase kinase kinase family [20,21]. TAK1 is thought to activate two divergent pathways that lead to the transcription factors NF-κB and AP-1 through kinase cascades involving the canonical IκB kinase complex (IKK- α, IKK-β, and IKK-γ) and MAP kinases (ERK, JNK, p38), respectively, to induce the expression of target genes. However, there is no evidence showing that TAK1 is really involved in these pathways in vivo. TIR-domain containing adapters MyD88 MyD88 was originally identified as one of the myeloid Structure of Toll/interleukin-1 receptor (TIR)-containing adapter differentiation primary response genes rapidly induced by proteins. DD, death domain. IL-6 in M1 myeloleukemic cells. MyD88 contains two domains characterized by a death domain and a TIR domain, but lacks a putative transmembrane region, suggesting that MyD88 might function as an adapter more alternative pathways leading to the expression of protein in cytoplasm (Fig. 2). Consequently, MyD88 was certain genes associated with the delayed activation of shown to be recruited to the IL-1R after IL-1 ligation and NF-κB and AP-1 probably exist in TLR4 signaling. In this to associate with IRAK1, resulting in the activation of regard, genes induced by LPS in a MyD88-independent transcription factors NF-κB and AP-1 [22–24]. Studies on manner were sought by subtractive screening, which MyD88-deficient mice clearly demonstrated that MyD88 is revealed that several genes were considerably induced an essential component in the responses to IL-1 and the after stimulation with LPS in MyD88-deficient cells [29]. IL-1-related cytokine IL-18 [25]. All of the responses to IL- These include interferon-inducible protein (IP)-10, a 1 and IL-18 and the activation of NF-κB and MAP kinases member of the CXC chemokines, glucocorticoid- were completely defective in cells from MyD88-deficient attenuated response gene 16 (GARG16) and immune- mice. Subsequent investigation confirmed that MyD88 is responsive gene 1 (IRG-1), all of which are so-called IFN- also used in TLR signaling. In MyD88-deficient mice, the inducible genes. Northern blot analyses showed that production of inflammatory cytokines such as tumor induction of these genes by LPS is comparable between necrosis factor-α, IL-1β and IL-6, the proliferation of B wild-type and MyD88-deficient macrophages, but is cells, and the induction of endotoxin shock in response to completely abolished in TLR4-deficient cells. Thus, there LPS (TLR4 ligand) are also completely abolished, is a MyD88-independent pathway that mediates the demonstrating that MyD88 is indispensable for the induction of IFN-inducible genes in TLR4 signaling [29]. responses to LPS in vivo [26]. In addition, cells from MyD88-deficient mice are totally unresponsive to peptido- The induction of some IFN-inducible genes is thought to glycan, lipoprotein, CpG DNA, and imidazoquinolines in be regulated in part by the transcription factor IRF3, a terms of cytokine production [12,27,28] (Fig. 3). member of the interferon regulatory factor (IRF) family. IRF3 is normally present in cytoplasm. Upon stimulation, In addition to inflammatory responses mediated by the IRF3 is phosphorylated at multiple serine residues to form MyD88-dependent pathway, a subset of TLRs can also a homodimer, moving to the nucleus, where it regulates induce appropriate responses depending on the types of the expression of IFN-β or other target genes [30]. IRF3- pathogens. In TLR4-deficient macrophages, all of the deficient mice are defective in the LPS-mediated induction responses to LPS tested are completely abolished, and of IFN-β and IFN-inducible genes but are intact in the the LPS-induced activation of NF-κB and MAP kinases production of inflammatory cytokines [31]. Furthermore, fails totally, indicating that TLR4 is an essential signaling the induction of some of IFN-inducible genes is regulated receptor for LPS [4,26]. In MyD88-deficient cells, the in part secondarily to LPS-inducible IFN-β, which binds to production of inflammatory cytokines and the activation of the IFN-α/β receptor and activates the classical IRAK1 in response to LPS are also diminished. However, JAK–STAT pathway [32,33]. These results suggest that NF-κB and MAP kinases are unexpectedly activated after IRF3 is responsible for the MyD88-independent induction stimulation with LPS in MyD88-deficient cells, but the of IFN-inducible genes. Indeed, IRF3 is normally activated activation was delayed in comparison with that in wild-type in response to LPS in MyD88-deficient cells [29,34]. cells [26]. In contrast, the activation of NF-κB and AP-1 in Thus, TLR4 is capable of inducing two different pathways, response to other stimuli such as ligands of TLR2, TLR5, namely the MyD88-dependent pathway responsible for TLR7, and TLR9 was completely defective in MyD88- the induction of a core set of inflammatory cytokines and 14 deficient cells. These aspects strongly suggest that one or the MyD88-independent pathway leading to the activation Available online http://arthritis-research.com/content/7/1/12 Figure 3 Schematic representation of Toll-like receptor (TLR) signaling pathways. All TLRs except for TLR3 are thought to share the MyD88-dependent pathway that activates NF-κB and mitogen-activated protein (MAP) kinases, leading to the induction of inflammatory cytokine genes. Interleukin-1 receptor-associated kinases (IRAKs) and TRAF6 are located downstream of MyD88. TIRAP is involved in the MyD88-dependent pathway downstream of TLR2 and TLR4. TRIF is utilized in the TLR3-mediated and TLR4-mediated activation of interferon regulatory factor (IRF)3 and the subsequent induction of IRF3-dependent gene expression such as interferon-β (IFN-β). TRAM is specifically involved in the activation of IRF3 in TLR4 signaling. The complex of TBK1/IκB kinase-i (IKK-i) is responsible for the activation of IRF3 downstream of TRIF in TLR3 and TLR4 signaling. TRAF6 is also involved in the TRIF-dependent activation of NF-κB and MAP kinases. Receptor-interacting protein (RIP) mediates TRIF-dependent NF-κB activation. DD, death domain. of IRF3 and IFN-β production (Fig. 3). In addition, TIRAP (MAL) stimulation with LPS also augments the surface The finding that a MyD88-independent pathway exists in expression of co-stimulatory molecules such as CD40, TLR4 signaling suggests that another protein, presumably CD80 and CD86 to induce the maturation of dendritic containing the TIR domain, acts downstream of TLR4 to cells (DCs) in MyD88-deficient mice, indicating that the activate IRF3 independently of MyD88. In this model, a maturation of DCs also proceeds without the MyD88- second TIR-domain-containing adapter TIRAP (also dependent pathway [35]. known as MAL) was identified by means of a database search, on the basis of the similarity to the TIR domain The MyD88-independent pathway is also used in TLR3 (Fig. 2) [36,37]. Expression of dominant-negative TIRAP, signaling. dsRNA (TLR3 ligand) also activates IRF3 and which encodes only the TIR domain, blocked NF-κB induces the expression of IFN-inducible genes, and these activation by TLR4 but not that by TLR9, and cell- inductions are normal in MyD88-deficient cells [34]. permeable peptide-mediated inhibition of TIRAP function Furthermore, the induction of IFN-inducible genes and the also decreased the induction of IP-10 by TLR4. Thus, activation of IRF3 are not observed after stimulation of TIRAP was expected to participate specifically in the macrophages with TLR2 ligands, showing the specific use TLR4-mediated MyD88-independent pathway. However, of the MyD88-independent pathway in TLR3 and TLR4 TIRAP-deficient mice were unexpectedly impaired in the signaling [29]. activation of NF-κB and MAP kinases and in the 15 Arthritis Research & Therapy Vol 7 No 1 Kawai and Akira production of inflammatory cytokines induced by TLR1, Downstream events of TRIF-dependent activation of NF- TLR2, TLR6, and TLR4 ligands [38,39]. In contrast, the κB are still unclear. It has recently been reported that TRIF TLR4-mediated maturation of DCs and the activation of associates directly with TRAF6 [44]. Three TRAF-binding IRF3 were intact in TIRAP-deficient mice. Taken together, motifs are present in the amino-terminal region of TRIF, these results indicate that TIRAP is unlikely to mediate the and a mutagenesis study demonstrated that these motifs MyD88-independent pathway; rather, it participates in the are necessary for association with TRAF6. Disruption of MyD88-dependent pathway downstream of TLR2 and TRAF-binding motifs in TRIF resulted in reduced activation TLR4 (Fig. 3). of NF-κB. Given that TRAF6 activates NF-κB but not the IFN-β promoter, TRIF activates NF-κB by recruitment of TRIF (TICAM1) TRAF6 via the TRAF-binding motifs [44]. In addition to A third TIR-domain containing the adapter TRIF (also amino-terminal TRAF-binding motifs, NF-κB is also known as TICAM1) was independently identified by the activated from the carboxy-terminal domain of TRIF, which database search and as an interacting partner with TLR3 lacks the TIR domain [40]. It has recently been reported by yeast two-hybrid screening (Fig. 2) [40,41]. Initial that the kinases receptor-interacting protein (RIP)-1 and studies indicated that the overexpression of TRIF strongly RIP3 are recruited to TRIF through the RIP homotypic activates the IFN-β-dependent promoter, in contrast to interaction motif (RHIM) found in the carboxy-terminal the lack of MyD88-mediated or TIRAP-mediated region of TRIF [45]. In cells deficient for the Rip1 gene, activation of the IFN-β-dependent promoter. TRIF, as well TLR3-mediated activation of NF-κB was selectively as MyD88 and TIRAP, also activates NF-κB after impaired, whereas activation of JNK or IFN-β promoter overexpression. Moreover, the expression of dominant- was intact, indicating that TLR3 uses RIP1 for activation of negative TRIF or the siRNA-mediated reduction of TRIF NF-κB downstream of TRIF; this was in contrast to other expression blocked TLR3-dependent activation of IRF3. TLRs, which use IRAKs for the activation of NF-κB (Fig. 3). These findings suggested that TRIF is involved in the MyD88-independent pathway. Subsequent generations TRAM (TICAM2, TIRP) of TRIF-deficient mice clearly revealed that they were The fourth TIR-domain-containing adapter was severely impaired in the induction of IFN-β and IFN- independently identified in the database search and termed inducible genes mediated by TLR3 and TLR4 ligands TRAM, TIRP, or TICAM2 (Fig. 2) [41,46,47]. It has recently [42]. Furthermore, activation of IRF3 was not observed in been demonstrated that responses of TRAM-deficient mice TRIF-deficient cells. Analyses of mutant mice designated to TLR2, TLR7, and TLR9 ligands are intact in terms of lps2, which were generated by N-ethyl-N-nitrosourea- production of inflammatory cytokines [48]. However, the induced random mutations, have also revealed that TRIF LPS (TLR4 ligand)-induced production of inflammatory is an lps2 gene product that is essential for responses cytokines was specifically impaired in TRAM-deficient mediated by TLR3 and TLR4 [43]. Thus, TRIF is a critical mice. Moreover, the induction of IFN-β and activation of protein that mediates the MyD88-independent pathway in IRF3 in response to LPS was severely impaired in TRAM- TLR3 and TLR4 signaling (Fig. 3). Furthermore, it is deficient mice, indicating that TRAM is also involved in the noteworthy that the production of inflammatory cytokines MyD88-independent pathway. These responses in TRAM- induced by LPS was severely impaired in both TRIF- deficient mice are very similar to those found in TRIF- deficient mice and MyD88-deficient mice. However, LPS- deficient mice, except for TLR3, to which TRAM-deficient induced activation of IRAK1 and early-phase activation of mice are normally responsive. Thus, TRAM specifically NF-κB and MAP kinases was normally found in TRIF- mediates the MyD88-independent pathway in TLR4 deficient cells; this is in contrast to MyD88-deficient cells, signaling but not in TLR3 signaling (Fig. 3). which show impaired activation of IRAK1 and late-phase activation of NF-κB and MAP kinases [29,42]. These Non-canonical IKKs findings strongly suggest that both the MyD88- The canonical IKKs (IKK-α and IKK-β) are required for the dependent and MyD88-independent pathways are activation of NF-κB mediated by TLRs and IL-1R [17]. required for the induction of genes for inflammatory These IKKs phosphorylate NF-κB inhibitor IκBs, leading to cyokines, whereas activation of the MyD88-independent the ubiquitination and degradation of IκBs by the (TRIF-dependent) pathway is sufficient to induce IRF3- proteasome pathway. NF-κB in turn translocates into the dependent IFN-β and IFN-inducible genes. In contrast, nucleus, where it induces the expression of target genes. activation of the MyD88-dependent pathway is sufficient Two kinases related to the canonical IKKs, TBK1 (also for the induction of inflammatory cytokines in the case of known as NAK and T2K) and IKK-i (also known as IKK-ε), TLR2, TLR5, TLR7, TLR9, and IL-1R. Thus, only TLR4 were identified [49,50]. These ‘non-canonical’ IKKs were uses both the MyD88-dependent and MyD88- also implicated in NF-κB activation, although the precise independent pathways for the induction of inflammatory mechanism is unclear. It has recently been shown that cytokines, although it remains unclear why both pathways forced expression of either TBK1 or IKK-i strongly 16 are necessary. enhances IFN-β-promoter-dependent reporter gene Available online http://arthritis-research.com/content/7/1/12 expression [51,52]. Furthermore, the kinase activities are these TLRs probably share the same signaling pathway. required for IFN-β-promoter activation, suggesting that Although there is still a need to characterize a specific TBK1/IKK-i activates IFN-β promoter by phosphorylating pathway that each TLR uses, understanding such one or more appropriate substrates. Indeed, TBK1/IKK-i is pathways will be therapeutically useful in the control of shown to be capable of phosphorylating the serine inflammatory and anti-viral responses. residues that are critical for activating IRF3 in vitro [51,52]. In cells deficient for the Tbk1 gene, the dsRNA- Roles of TLRs in the pathogenesis of rheumatoid arthritis mediated or LPS-mediated activation of IRF3 (dimer have been investigated. It was demonstrated that formation, nuclear localization) and induction of IRF3- peptidoglycan and bacterial DNA, which is recognized by dependent genes such as IFN-β, GARG16 and IP-10 TLR2 and TLR9, could be detected in the synovium of were considerably reduced, whereas the induction of patients with rheumatoid arthritis [58]. Furthermore, inflammatory cytokines, which is regulated by the MyD88- synovial cells express low levels of TLR2 and TLR9, and dependent pathway and activation of NF-κB and MAP TLR2 is upregulated by exposure to peptidoglycan [59,60]. kinases, was not impaired [53]. Thus, TBK1 is specifically In addition, TLRs have been shown to recognize involved in the induction of IRF3-dependent genes endogenous ligands present in tissues and cells in the mediated by TLR3 and TLR4 (Fig. 3). In contrast, IKK-i- absence of bacterial infection. TLR2 activates cells through deficient cells normally respond to LPS and dsRNA to the recognition of heat shock protein 70 and necrotic cells, induce both IRF3-dependent and NF-κB-dependent gene both of which are detected in synovial tissue of patients expression. However, in TBK1/IKK-i doubly deficient cells with rheumatoid arthritis [61]. These findings suggest that the residual induction of IFN-inducible genes found in TLRs contribute to the pathogenesis of rheumatoid TBK1-deficient cells was completely abolished, indicating arthritis, and targeting the TLR signaling pathway will raise that IKK-i also participates in the pathway dependent on the possibility of a drug discovery to control inflammation TLR3 and TLR4 [54]. It has recently been reported that induced in patients with rheumatoid arthritis. TRIF also binds TBK1 through the amino-terminal region which shares the binding with TRAF6, and the association Competing interests between TRIF and TBK1 seems to require the kinase The author(s) declare that they have no competing interests. activity of TBK1 [44]. Furthermore, expression of the kinase-negative mutant of TBK1 significantly blocked Acknowledgements We thank members of the Akira laboratory for helpful discussions, and TRIF-dependent activation of the IFN-β promoter, thus M. Hashimoto for her excellent secretarial assistance. indicating that TBK1 and IKK-i act downstream of TRIF. TBK1 and IKK-i also bind TANK (also known as I-TRAF) References and a newly identified TANK-related protein NAP1 1. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA: The dorsoventral regulatory gene cassette spatzle/Toll/cactus [49,55,56]. 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Journal

Arthritis Research & Therapy – Springer Journals

Published: Nov 1, 2004

Keywords: Rheumatology; Orthopedics

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