Immunity against microbial pathogens primarily depends on the recognition of pathogen components by innate receptors expressed on immune and non-immune cells. Innate receptors are evolutionarily conserved germ-line-encoded proteins and include TLRs (Toll-like receptors), RLRs [RIG-I (retinoic acid-inducible gene-I)-like receptors] and NLRs (Nod-like receptors). These receptors recognize pathogens or pathogen-derived products in different cellular compartments, such as the plasma membrane, the endosomes or the cytoplasm, and induce the expression of cytokines, chemokines and co-stimulatory molecules to eliminate pathogens and instruct pathogen-specific adaptive immune responses. In the present review, we will discuss the recent progress in the study of pathogen recognition by TLRs, RLRs and NLRs and their signalling pathways.

INTRODUCTION

The innate immune system is the first line of the defence system against microbial pathogens such as Gram-positive and Gram-negative bacteria, fungi and viruses. Innate immune cells such as macrophages and DCs (dendritic cells) directly kill the pathogenic micro-organism through phagocytosis or induce the production of cytokines, which aid elimination of the pathogens [1,2,34]. The responses of the innate immune system instruct the development of long-lasting pathogen-specific adaptive immune responses. The adaptive immune system consists of B- and T-cells, which provide pathogen specific immunity to the host through somatic rearrangement of antigen receptor genes. B-cells produce pathogen-specific antibodies to neutralize toxins produced by pathogens, whereas T-cells provide the cytokine milieu to clear pathogen-infected cells through their cytotoxic effects or via signals to B-cells [5].

The mechanisms for innate immune recognition of pathogens and signalling have received increasing research attention. These studies were initiated after the discovery of Toll protein, which plays an important role in the defence against fungal infection in Drosophila (fruitfly) [6]. Further studies led to the discovery of the TLR (Toll-like receptor) family of proteins in mammals [7,89]. Recently, other proteins families such as RLRs [RIG-I (retinoic acid-inducible gene-I)-like receptors] [1,10] and NLRs (Nod-like receptors) [1,11,1213] were discovered. These families of receptors are collectively known as PRRs (pattern-recognition receptors) [14], which recognize the specific molecular structures of pathogens known as PAMPs (pathogen-associated molecular patterns) in various compartments of cells, such as the plasma membrane, the endolysosome and the cytoplasm.

In the present review we will focus on recent advances in the study of recognition and signalling mediated by TLRs, RLRs and NLRs.

TOLL-LIKE RECEPTORS

The Toll protein was originally identified in fruitflies (Drosophila) and is involved in dorsoventral polarity during embryonic development [6]. Further studies have shown that the Toll protein plays an essential role in mounting an effective immune response against the fungus Aspergillus fumigatus [6]. These studies led to the identification of homologues of Toll proteins in humans and mice through database searches and which are referred to as TLRs [7]. To date, 10 and 13 TLR members have been identified in humans and mice respectively [1]. The TLRs are type I membrane glycoproteins and consist of an extracellular LRR (leucine-rich repeat) domain, a transmembrane domain and a cytoplasmic TIR]Toll/IL (interleukin)-1 receptor] domain [15]. The LRR domain of TLRs consists of 16–28 tandem repeats of the LRR motif [16] and is involved in the recognition of ligands such as protein (e.g. flagellin and porin from bacteria), sugar (e.g. zymosan from fungi), lipid [LPS (lipopolysaccharide), lipid A and LTA (lipoteichoic acid) from bacteria], nucleic acid (CpG-containing DNA from bacteria and viruses and viral RNA), derivatives of protein or peptide (lipoprotein and lipopeptides from various pathogens), derivatives of lipid (lipoarabinomannan) from mycobacteria) and a complex derivative of protein or peptides, sugar and lipid (diacyl lipopeptides from mycoplasma) [1]. The TIR domain of TLRs consists of approx. 150 amino acids and shows homology with the cytoplasmic region of the IL-1 receptor. Therefore, it is termed the TIR domain [15,17]. The TIR domain interacts with TIR-domain-containing adaptors such as MyD88 (myeloid differentiation primary response gene 88), TIRAP [TIR-containing adaptor protein, also known as MAL (MyD88-adaptor-like], TRIF [TIR-containing adaptor-inducing IFN (interferon)-β, also known as TICAM1 (TIR-domain-containing adaptor molecule 1] and TRAM (TRIF-related adaptor molecule, also known as TICAM2). In turn, the downstream signalling pathways activate MAPKs (mitogen-activated protein kinases) and transcription factors such as NF-κB (nuclear factor κB) and IRFs (IFN regulatory factors) to induce production of inflammatory cytokines and type I IFNs.

The TLR family members are expressed on various immune and non-immune cells such as B-cells, NK (natural killer) cells, DCs, macrophages, fibroblast cells, epithelial cells and endothelial cells. However, TLRs are differentially localized within the cells. TLR1, TLR2, TLR4, TLR5 and TLR6 are expressed on the cell surface, whereas TLR3, TLR7, TLR8 and TLR9 are expressed in the endosomes (Figure 1).

PAMPs recognized by TLRs and their adaptors

Figure 1
PAMPs recognized by TLRs and their adaptors

Plasma-membrane-localized TLRs (TLR2, TLR4, TLR5, TLR11 alone and TLR2 in association with TLR1 or TLR6) and endosomally localized TLRs (TLR3, TLR7 and TLR9) recognize the indicated ligands. TLR1, TLR2, TLR4 and TLR6 recruit TIRAP and MyD88. MyD88 also contains the DD. In addition to TIRAP and MyD88, TLR4 recruits TRAM and TRIF. TLR5, TLR7, TLR9 and TLR11 recruit MyD88, whereas TLR3 recruits TRIF.

Figure 1
PAMPs recognized by TLRs and their adaptors

Plasma-membrane-localized TLRs (TLR2, TLR4, TLR5, TLR11 alone and TLR2 in association with TLR1 or TLR6) and endosomally localized TLRs (TLR3, TLR7 and TLR9) recognize the indicated ligands. TLR1, TLR2, TLR4 and TLR6 recruit TIRAP and MyD88. MyD88 also contains the DD. In addition to TIRAP and MyD88, TLR4 recruits TRAM and TRIF. TLR5, TLR7, TLR9 and TLR11 recruit MyD88, whereas TLR3 recruits TRIF.

Recently, co-crystallization of TLR1–TLR2, TLR3 and TLR4 and their ligand-recognition properties has been reported. The heterodimer or homodimer of the LRR domain of TLR1–TLR2, TLR4 and TLR3 show a horseshoe-like structure or m-shaped framework and consists of both a concave and a convex surface. These surfaces are responsible for ligand binding and ligand-induced TLR dimerization [18,19,2021].

Pathogen recognition by the extracellular cell-surface TLRs

TLR1, TLR2 and TLR6

TLR2 recognizes a structurally diverse range of PAMPs that include proteins such as V-antigen (LcrV) from Yersinia, haemagglutinin protein from measles virus, glycolipids, LTA from Staphylococcus aureus and Streptococcus pneumoniae [22], lipopeptides or lipoproteins such as MALP (macrophage-activating lipopeptide)-2 and R-MALP from Mycoplasma species [23,2425], lipoproteins from Escherichia coli [26], Borrelia burgdorferi [27], Mycoplasma species [28] and Mycobacterium tuberculosis [29], peptidoglycan from Staph. aureus, Strep. pneumoniae and Strep. pyogenes [30,3132] and polysaccharides known as zymosan from Saccharomyces cerevisiae [33,34]. The ligands for TLR2 have been described in detail in a review article [35]. In addition, TLR2 also recognizes complete pathogens, including the species of the bacterium Chlamydia [36], viruses such as HSV (herpes simplex virus) [37] and varicella-zoster virus [38] (Figure 1). The diversity of ligand recognition by TLR2 is possible because TLR2 can recognize the ligands in association with structurally related TLRs such as TLR1 and TLR6. The TLR2–TLR1 and TLR2–TLR6 heterodimers recognize triacyl lipopeptide derived from Gram-negative bacteria and diacyl lipopeptide derived from mycoplasma respectively [39,40]. TLR2 also recognizes zymosan (β-1,3-glucan and β-1,6-glucan) in association with the structurally unrelated C-type lectin family known as dectin-1 [41]. Furthermore, the class II scavenger receptor CD36 has been shown to be involved in phagocytosis and cytokine production in response to Staph. aureus and its cell-wall components such as LTA and MALP-2, suggesting that CD36 functions as a co-receptor of TLR2/6 [25].

TLR4

TLR4 recognizes LPS from Gram-negative bacteria [8,9], glycoinositolphospholipids from Trypanosoma [42], the fusion protein from RSV (respiratory syncytial virus) [43] and the envelope protein from MMTV (mouse mammary tumour virus) [44]. TLR4 also recognizes diterpene (taxol) purified from the bark of Taxus brevifolia (the Pacific yew) [45,46] (Figure 1). In addition, TLR4 directly or indirectly recognizes endogenous molecules such as heat-shock proteins, fibrinogen, hyaluronic acid, β-defensin and extracellular domain A in fibronectin [47]. The recognition of LPS is triggered by a complex that contains TLR4, a recognition subunit MD2 (myeloid differentiation protein-2) and membrane-bound GPI (glycosylphosphatidylinositol)-anchored CD14. The activation of TLR4 is further supported by another protein known as LBP (LPS-binding protein) [48]. The studies show that the lipid A (an active component of LPS) binds to MD2 and forms a complex. The lipid A–MD2 complex interacts with TLR4 and activates signalling, suggesting that MD2 is more important in the recognition of lipid A [18].

TLR5

TLR5 recognizes a monomer of flagellin [49], an important structural protein of pathogenic and non-pathogenic motile bacteria. It is also important for adhesion and invasion at the luminal surface of the epithelial cells covering the mucosal tissues during infection [50]. Flagellin from Salmonella typhimurium contains 494 amino acids and consists of two functional domains. The 140 amino acids of the N-terminal domain and 90 amino acids of the C-terminal domain of this protein are highly conserved and essential for the polymerization and motility of flagellin [51]. The central domain of the protein is highly variable among Salmonella serovars and bacterial species, and this region is exposed at the outer surface of the flagellum. Amino acids 89–96 are essential for TLR5 activation, but this region is located deep inside the tertiary structure of the flagellin protein and becomes accessible only when flagellin is present in monomer form [52,53]. However, it is not clear how flagellated bacteria deliver monomeric flagellin under physiological conditions. TLR5 is mainly expressed on the luminal surface of the epithelial cells covering the mucosal tissues and trachea, and the bronchi and the alveoli of the respiratory tract [54,55,56,5758] (Figure 1). Upon activation with flagellin, epithelial cells induce cytokines and chemokines, and neutrophil recruitment. Recently, we have shown that TLR5+ small-intestinal LPDCs (lamina propria DCs) are important for the induction of humoral and cellular immunity in the intestine. These LPDCs can induce retinoic acid and are involved in the generation of IgA+ plasma cells, as well as the differentiation of both Th1 (T-helper 17) and Th1 cells in the intestine in a TLR5-dependent manner [59].

TLR11

TLR11 recognizes profilins from Toxoplasma gondii, an obligate intracellular protozoan parasite [60]. It also recognizes uropathogenic E. coli (Figure 1). Mice deficient in TLR11 show increased susceptibility to these pathogens [61]. TLR11 has been shown to be expressed on epithelial cells of the bladder in mouse. However, TLR11 is not expressed in humans, as the predicted mRNA has at least one stop codon [62].

Pathogen recognition by intracellular TLRs

TLR3

TLR3 recognizes viral ds (double-stranded) RNA originating from dsRNA viruses such as reovirus [63]. TLR3 also recognizes dsRNA produced during replication of ss (single-stranded) RNA viruses, such as WNV (West Nile virus) [64], RSV [65] and EMCV (encephalomyocarditis virus) [66]. In addition, TLR3 recognizes a synthetic analogue of dsRNA known as poly(I-C) (Figure 1). TLR3 is expressed in the endosomes of immune cells, including cDCs (conventional DCs – a type of antigen-presenting cell that induces various cytokines after stimulation with ligands), macrophages, B-cells, NK cells and non-immune cells, including epithelial cells. However, TLR3 is not expressed on pDCs (plasmacytoid DCs – a type of DC that produces high amounts of type I IFNs). In addition, TLR3 is highly expressed in the brain [67]. TLR3-deficient mice infected with various RNA viruses such as MCMV (murine cytomegalovirus), VSV (vesicular-stomatitis virus), LCMV (lymphocytic choriomeningitis virus), RSV or reovirus show comparable susceptibility with WT (wild-type) mice, suggesting that TLR3 is dispensable for protection against these viruses [68]. However, TLR3-deficient mice infected with lethal doses of WNV show resistance to the WNV infection, suggesting that TLR3-mediated inflammatory responses induce death of the mice [69]. Therefore, the role of TLR3 in viral infection is unclear.

TLR7, TLR8 and TLR9

TLR7, TLR8 and TLR9 are located in the intracellular endosomal compartment, where they sense microbial nucleic acids such as RNA and DNA. TLR7 and TLR8 (but not mouse TLR8) respond to synthetic antiviral imidazoquinoline compounds such as R848, loxoribine and imiquimod and ssRNAs rich in guanosine or uridine derived from viruses [70,7172] (Figure 1). Generally, these viruses gain entry into cells through receptor-mediated endocytosis and reach the phagolysosome, where the virus-coat protein is hydrolysed to expose the viral RNA to the TLRs. In contrast, the host ssRNA does not reach the endocytic vesicles because it is degraded by RNase.

TLR9 recognizes unmethylated CpG motifs of ssDNA and induces inflammatory cytokines and type I IFNs. These sequences are commonly present in the genomes of bacteria and viruses [73,74,75,7677]. However, in the host, these sequences are highly methylated at the cytosine base and, therefore, the host CpG motifs stimulate poorly. Synthetic ssDNA-containing CpG dinucleotides motifs can also induce the production of inflammatory cytokines and type I IFNs through TLR9. There are two structurally distinct types of CpG DNAs known, namely the A-type (D-type) and the B-type (K-type). A-type CpG ODNs (oligodeoxynucleotides) stimulate pDCs to induce a robust amount of IFN-α and a little IL-12 [78]. By contrast, B-type CpG ODN is a potent inducer of inflammatory cytokines such as IL-6, IL-12 and TNF-α (tumour necrosis factor-α) and up-regulates co-stimulatory molecules such as CD80, CD86 and MHC class II in pDCs and, to lesser extent, in B-cells [79]. DNA viruses such as MCMV, HSV (herpes simplex virus)-1 and HSV-2 induce inflammatory cytokines and type I IFNs through TLR9 [73,74,75,7677]. It has been shown that TLR9-deficient mice are susceptible to MCMV infection [76]. HSV recognition by pDCs does not require viral replication, because UV-inactivated virus still induces IFN-α [75]. In addition to these ligands, TLR9 also recognizes the malarial pigment known as haemozoin [80]. Recently, it was shown that cleavage of TLR9 by lysosomal cathepsins is involved in the activation of signalling [81,8283].

Signalling through TLR

Upon recognition, TLRs recruit various TIR-domain-containing adaptors to the TIR domain of TLRs. TLR5, TLR7, TLR9 and TLR11 only use MyD88. TLR1, TLR2, TLR4 and TLR6 use TIRAP in addition to MyD88, which links TLR to MyD88. TLR3 only uses TRIF. TLR4 uses TRIF and TRAM, and TRAM links TLR4 with TRIF. Taken together, TLR signalling can be broadly divided into two signalling pathways: the MyD88-dependent and TRIF-dependent pathways [1,17,47,84,85] (Figures 1 and 2).

In the MyD88-dependent signalling pathway, the IRAK (IL-1 receptor-associated kinase) family members such as IRAK4, IRAK1 and IRAK2 are recruited to the MyD88. IRAK4 is initially activated, and IRAK1 and IRAK2 are sequentially activated [86]. The activated IRAK family proteins associate with TRAF6 (TNF receptor-associated factor 6), an E3 ubiquitin ligase, which forms a complex with E2 ubiquitin-conjugating enzymes such as UBC13 (ubiquitin C 13) and UEV1A (ubiquitin-conjugating enzyme variant 1A). This complex polyubiquitinates TRAF6 itself and IKKγ [IκB kinase γ, also known as NEMO (NF-κB essential modifier)] through K63 (Lys63) linkage [87,88]. The polyubiquitinated TRAF6 activates the protein kinase TAK (transforming growth factor-β-activated kinase 1) and TABs (TAK1-binding proteins) such as TAB1, TAB2 and TAB3, which subsequently activate transcription factors such as NF-κB and AP-1 (activator protein-1) through the canonical IKK complex and the MAPK [ERK (extracellular-signal-regulated kinase), JNK (c-jun N-terminal kinase) and p38] pathway respectively for the transcription of inflammatory cytokine genes [87]. TAK1-deficient cells show reduced inflammatory cytokine levels and impaired NFκB and MAPK activation after stimulation with various TLR ligands [89,90]. TLR4 also activates NF-κB via TRIF by two distinct signalling pathways [91]. The N-terminus of TRIF interacts with TRAF6 through the TRAF6-binding motifs [92] and the C-terminus of TRIF interacts with RIP1 (receptor-interacting protein 1), both of which co-operate to activate NF-κB [93] (Figure 2). Recently, we showed that the TRIF-dependent signalling pathway is negatively regulated by Atg16L1 (autophagy-related 16-like 1). Mice lacking Atg16L1 show enhanced production of cytokine, suggesting an essential role for autophagy in innate immune regulation [94].

TLR signalling in conventional DCs or macrophages

Figure 2
TLR signalling in conventional DCs or macrophages

The engagement of TLRs with their respective ligands initiates signalling. MyD88 recruits the IRAK family of proteins and TRAF6. TRAF6 activates TAK1 which, in turn, activates the IKK complex consisting of IKKα, IKKβ and NEMO/IKKγ, and phosphorylates IκBs. Phosphorylated IκBs are ubiquitinated and undergo proteasome-mediated degradation, and NF-κB subunits, which consist of p50 and p65, translocate to the nucleus. TAK1 also activates the MAPK signalling pathway. The activated NF-κB and MAPK initiate the transcription of inflammatory cytokine genes. TRIF recruits RIP1 and TRAF6. Activated TRAF6 and RIP1 activate NF-κB and MAPK to induce transcription of inflammatory cytokine genes. TRIF interacts with TRAF3 and activates TBK1/IKKi, which phosphorylate IRF3 and IRF7. The phosphorylated IRF3 and IRF7 are translocated to the nucleus for the transcription of type I IFNs.

Figure 2
TLR signalling in conventional DCs or macrophages

The engagement of TLRs with their respective ligands initiates signalling. MyD88 recruits the IRAK family of proteins and TRAF6. TRAF6 activates TAK1 which, in turn, activates the IKK complex consisting of IKKα, IKKβ and NEMO/IKKγ, and phosphorylates IκBs. Phosphorylated IκBs are ubiquitinated and undergo proteasome-mediated degradation, and NF-κB subunits, which consist of p50 and p65, translocate to the nucleus. TAK1 also activates the MAPK signalling pathway. The activated NF-κB and MAPK initiate the transcription of inflammatory cytokine genes. TRIF recruits RIP1 and TRAF6. Activated TRAF6 and RIP1 activate NF-κB and MAPK to induce transcription of inflammatory cytokine genes. TRIF interacts with TRAF3 and activates TBK1/IKKi, which phosphorylate IRF3 and IRF7. The phosphorylated IRF3 and IRF7 are translocated to the nucleus for the transcription of type I IFNs.

Stimulation with TLR4 and TLR3 ligands activates the TRIF-dependent signalling pathway and induces inflammatory cytokines in addition to type I IFNs and IFN-inducible genes in DCs and macrophages, which depend on IRF3 and IRF7. The production of type I IFNs is absent in TRIF-deficient cells [95]. IRF3 and IRF7 are activated by IKK-related kinase TBK1 [TANK binding kinase 1, also known as T2K (TRAF2-associated kinase) or NAK (NF-κB activating kinase)] and IKKi (also known as IKKε) [96,97]. TBK1 and IKKi interact with TANK (TRAF family member-associated NF-κB activator), NAP1 (NAK-associated protein 1) and, similar to NAP1, SINTBAD (TBK1 adaptor), which then phosphorylates IRF3 and IRF7. Phosphorylated IRF3 and IRF7 form a homodimer, which subsequently translocates into the nucleus and binds to the ISREs (IFN-stimulated response elements) to induce type I IFNs and IFN-inducible genes [98]. TRAF3 has been proposed to link TRIF to TBK1, because TRAF3 interacts with these proteins and the production of IFN-β is abrogated in TRAF3-deficient cells [99,100] (Figure 2).

In pDCs, TLR7 and TLR9 are highly expressed and induce a huge amount of type I IFNs, particularly IFN-α, after virus infection. Upon stimulation, MyD88 forms a complex with IRF7 [101,102] (which is highly expressed in pDCs) and TRAF6 to induce the production of type I IFNs [100]. IRAK1 interacts with MyD88 and can phosphorylate IRF7 [103]. IRAK1-deficient pDCs consistently have defects in type I IFN production, but show intact inflammatory cytokine production. Similarly, the production of type I IFNs is decreased in IKKα-deficient mice, and IKKα can bind to, and phosphorylate, IRF7 [104]. These findings suggest that IRAK1 and IKKα act as IRF7 kinases. By contrast, pDCs lacking MyD88 or IRAK4 do not induce type I IFNs and inflammatory cytokines. Taken together, these observations suggest that the TLR7– or TLR9–MyD88–TRAF6–IRAK4–IRAK1–IKKα–IRF7 signalling pathway is active in pDCs for the robust production of type I IFNs after virus infection (Figure 3). Recently, the involvement of the serine/threonine protein kinase mTOR (mammalian target of rapamycin) and its downstream signalling kinases, such as the p70 ribosomal S6 protein kinases p70S6K1 and p70S6K2, has been shown to play roles in pDC for the production of type I IFNs. Inhibition of mTOR and its downstream kinases blocks the interaction between TLR9 and MyD88 and inhibits further activation of IRF7 [105].

TLR signalling in pDCs

Figure 3
TLR signalling in pDCs

TLR7 and TLR9, which are associated with UNC-93B, are transported to the endolysosome. In the endolysosome, these TLRs interact with their respective ligands and recruit MyD88. MyD88 interacts with TRAF6 through IRAK4 and activates TAK1. TAK1 activates NF-κB through the IKK complex. MyD88 also interacts with IRAK4 and IRAK1. The IRAK1 and IKKα phosphorylate IRF7. IRAK1 interacts with TRAF3 and phosphorylates IRF7. The phosphorylated IRF7 is translocated to the nucleus for the transcription of type I IFNs.

Figure 3
TLR signalling in pDCs

TLR7 and TLR9, which are associated with UNC-93B, are transported to the endolysosome. In the endolysosome, these TLRs interact with their respective ligands and recruit MyD88. MyD88 interacts with TRAF6 through IRAK4 and activates TAK1. TAK1 activates NF-κB through the IKK complex. MyD88 also interacts with IRAK4 and IRAK1. The IRAK1 and IKKα phosphorylate IRF7. IRAK1 interacts with TRAF3 and phosphorylates IRF7. The phosphorylated IRF7 is translocated to the nucleus for the transcription of type I IFNs.

The ER (endoplasmic reticulum)-localized transmembrane protein known as UNC93B1 was shown to be essential for the production of inflammatory cytokines after stimulation with TLR3, TLR7 and TLR9 ligands [106]. In addition, UNC93B1 plays a crucial role in the cross-presentation of an exogenous antigen via MHC Class I and Class II. Moreover, UNC93B1 is required for the translocation of TLR7 and TLR9 from the ER to the endolysosome [107,108109].

TLR and human diseases

Genetic variations or a deficiency of genes encoding TLR and TLR signalling proteins have been implicated in the predisposition to innate immune diseases [110]. Recently, autosomal recessive MyD88-deficient pediatric patients have been reported. These patients show susceptibility to pyrogenic bacterial infections such as Strep. pneumoniae and Staph. aureus, and severe complications have been reported in several patients in early childhood. Otherwise, these patients are healthy and have normal immunity to other microbes, and their clinical severity improves with age. These observations suggest that MyD88-dependent signalling is essential for protective immunity against a few types of pyrogenic bacteria, but is dispensable for the host defence to the majority of other infections in humans [111].

IRAK4 deficiency has also been reported in humans. The IRAK4 gene is located on an autosomal chromosome and 28 individuals with a recessive gene have been reported so far. These patients show increased susceptibility to infection by Gram-positive and Gram-negative bacteria in early childhood [112]. Similar to MyD88 deficiency or mutants, IRAK4-deficient people also show an improvement in symptoms with advancing age. These patients also show impaired induction of type I IFNs, but do not show any susceptibility to viral infection or HSE (herpes simplex virus encephalitis). Furthermore, these individuals do not show susceptibility to any parasitic or fungal diseases. Patients with TLR3 deficiency have also been reported. These patients show increased susceptibility to HSV-1 [113]. These observations suggest that TLRs play an important role in the pathogenesis of some diseases. UNC93B deficiency has also been documented in some patients. Cells from these patients do not respond to TLR3, TLR7, TLR8 or TLR9. However, similar to IRAK4-deficient patients, UNC93B patients do not show susceptibility to viral diseases such as HSE [114].

RIG-I-LIKE RECEPTORS

Much progress has been made in TLR-independent recognition of viral nucleic acids, particularly RNA recognition by intracellular sensors [1,115,116,117118]. The intracellular sensors are important for the detection of RNA derived from RNA viruses and replicating DNA viruses. The recognition of RNA by intracellular sensors subsequently activates innate antiviral responses, mainly through the induction of type I IFNs and inflammatory cytokines in most cell types.

In this regard, DExD/H-box RNA helicase, known RIG-I, was found to have a role in the cytoplasmic recognition of dsRNA and activation of IRFs and NF-κB [119]. Two members of this family known as Mda5 (melanoma differentiation-associated gene 5) and Lgp2 (Laboratory of Genetics and Physiology 2) were subsequently identified [120]. These proteins are collectively known as RLRs. RIG-I and Mda5 contain two tandem repeats of the CARD (caspase recruitment domain) at their N-terminus, which are important for activating downstream signalling. The intermediate portion of these proteins contains the helicase domain, which is similar to other members of the DExD/H-box RNA helicase family. For RIG-I, this domain contains an ATP-binding region, which is essential for RIG-I function. However, an ATP-binding region was not found in Mda5. In addition, RIG-I contains an RD (repressor domain) at the C-terminus, which represses the activity of RIG-I [121,122]. Repression of Mda5 in the steady state is not known, but it has been postulated that MdA5 might be negatively regulated by other proteins such as DAK (dihydroacetone kinase) [123]. Lgp2 contains the RNA helicase domain, but is devoid of the CARD. This protein was considered to be a negative regulator for RIG-I and Mda5. However, a study of Lgp2-deficient mice revealed that Lgp2 acts as both a negative and positive regulator depending on the virus [124]. Recently, a homologue of RIG-I helicase (DExD/H-box helicase), Dicer-2, was identified in Drosophila and which controls the expression of an antiviral protein known as Vago after virus infection, suggesting an evolutionarily conserved role of RLR in antiviral responses [125].

Pathogen recognition by RLRs

Studies of RIG-I- and Mda5-deficient mice revealed that these sensors recognize different classes of RNA viruses. RIG-I-deficient cells infected with NDV (Newcastle-disease virus), VSV, SeV (Sendai virus) and IV (influenza virus) show impaired type I IFN and inflammatory cytokine production [126,127]. Furthermore, members of the flavivirus family, such as JEV (Japanese encephalitis virus) and HCV (hepatitis C virus) are also recognized by RIG-I [128,129]. However, dengue virus and WNV, which belong to the flavivirus family, do not require RIG-I. By contrast, Mda5-deficient mice show normal production of type I IFNs and inflammatory cytokines against NDV, VSV, SeV, IV and JEV. However, they show impaired ability to produce type I IFNs and inflammatory cytokines against picornaviruses such as EMCV, Theiler's virus and Mengo virus [128]. These observations suggest that these two sensors induce antiviral responses against a wide spectrum of RNA viruses with different specificity. However, RLRs are not sufficient for the protection against other RNA viruses such as IV, RSV and LCMV In vivo. In other words, In vivo infection of LCMV induces the production of type I IFNs and the promotion of virus-specific CD8 T-cells through the TLR7 rather than the RLR signalling pathway [130]. For IV infection, the RLR signalling pathway is essential for the induction of cytokines in fibroblasts, alveolar macrophages, and cDCs, whereas TLR7 acts in pDCs to induce cytokines [131,132]. However, the production of virus-specific antibodies is dependent on TLR7 rather than RLR. Similar observations were reported for RSV infection [133], suggesting that TLR and RLR signalling pathways together induce the host defence against these viruses. Moreover, co-operative activation of TLR and RLR is also required for the adjuvant effects of poly(I-C) [134].

RIG-I and Mda5 recognize in-vitro-synthesized dsRNA and a synthetic analogue of dsRNA poly(I-C) respectively [128]. Further studies revealed that the 5′-triphosphate moiety of RNA is essential for RIG-I recognition [135] and it is independent of the strand property (single or double) of RNA [136]. A recent biochemical study revealed that the 5′-triphosphate moiety of RNA is recognized by the CTD (C-terminal domain) of RIG-I [122]. Host-cell RNA is not recognized by RIG-I because, during synthesis of cellular RNA, the 5′-ends are either modified by the addition of a 7-methylguanosine cap or the 5′-triphosphate is removed before transportation to the cytoplasm. Thus RIG-I can discriminate between viral and host RNA. RIG-I can bind to a 25-bp dsRNA to efficiently induce type I IFNs and the RNA end structures (blunt end, 5′-overhang and 3′-overhang), and the nucleotide sequences are not critical for binding to RIG-I [137]. Furthermore, it has been shown, using NMR of the CTD, that RIG-I recognizes two distinct viral RNA patterns, including ds and 5′-triphosphate ssRNA, and gel-filtration analysis revealed that a dimer of RIG-I CTD mediates the recognition of 5′-triphosphate RNA [118]. The length of dsRNA is critical for differential recognition by RIG-I and Mda5; RNA viruses have a shorter RNA length (approx. 1.2–1.4 kbp) and are recognized by RIG-I, whereas viruses with longer dsRNA (longer than 3.4 kbp) are recognized by Mda5 [138].

SIGNALLING THROUGH RLRs FOR ANTIVIRAL RESPONSES

In response to viral infection, the CARDs of RIG-I and Mda5 associate with the CARD-containing adaptor protein known as IPS-1 {IFN promoter stimulator-1, also known as MAVS (mitochondrial antiviral signalling), Cardif (CARD adaptor inducing IFN-β) and VISA (virus-induced signalling adaptor [139,140,141142]} to induce inflammatory cytokines and type I IFNs. Ectopic expression of IPS-1 in cells activates NF-κB and IFN promoters. In addition, IPS-1-deficient cells show a complete abrogation of inflammatory cytokines and type I IFNs after virus infection. Furthermore, IPS-1-deficient mice infected with various RNA viruses recognized by RIG-I and Mda5 show enhanced motility compared with that in WT mice [143,144]. These observations collectively suggest that IPS-1 is the sole adaptor for RIG-I/Mda5 and plays an essential role in host defence against various RNA viruses. It has been shown that IPS-1 is localized in the outer membrane of mitochondria [140]. NS3/4 (non-structural 3/4) protease from HCV cleaves and dislodges IPS-1 from the mitochondria to block IFN production, suggesting that mitochondrial localization is essential for IPS-1 function with respect to antiviral responses [141]. The NLR family protein known as NLRX1 was recently reported to be localized in the outer membrane of mitochondria and to inhibit IPS-1-mediated type I IFN induction in response to virus infection [145]. Signalling through RIG-I is further regulated by ubiquitination. It was shown that TRIM25 (tripartite motif 25), a ubiquitin E3 ligase which contains an RNF (RING-finger) domain, a B-box/coiled-coil domain and a SPRY (SPla/RYanodine) domain, interacts with the N-terminal CARD of RIG-I. This interaction leads to the Lys63-linked ubiquitination of RIG-I. Furthermore, TRIM25-deficient cells show abrogation of type I IFNs production, suggesting that ubiquitination of RIG-I is essential for activation of the signalling pathway[146]. By contrast, RIG-I is inhibited by another ubiquitin ligase, RNF125, which induces ubiquitination and proteasomal degradation of RIG-I. These observations suggest that the ubiquitination is an additional regulatory mechanism for the RIG-I-mediated signalling pathway [147] (Figure 4).

Recognition of RNA and RNA viruses by RLRs

Figure 4
Recognition of RNA and RNA viruses by RLRs

Viral RNA, ssRNA, dsRNA and dsRNA analogue poly(I-C) are recognized in the cytoplasm of cDCs, macrophages and fibroblast cells by RIG-I and Mda5. Upon recognition, the CARD of Mda5 and ubiquitinated CARD of RIG-I bind to IPS-1 (located on the outer membrane of mitochondria). The CARD of RIG-I undergoes ubiquitination by TRIM25. IPS-1 then interacts with TRADD and forms a complex with FADD and caspase 8/10 to activate NF-κB through the IKK complex. TRADD also interacts with TRAF3 and activates TBK1/IKKi, which phosphorylates IRF3 and IRF7 to induce the transcription of type I IFNs. The mitochondrial NLRX1 inhibits IPS-1-mediated signalling. Mitochondrially localized STING interacts with RIG-I and IPS-1 and activates NF-κB and IRFs.

Figure 4
Recognition of RNA and RNA viruses by RLRs

Viral RNA, ssRNA, dsRNA and dsRNA analogue poly(I-C) are recognized in the cytoplasm of cDCs, macrophages and fibroblast cells by RIG-I and Mda5. Upon recognition, the CARD of Mda5 and ubiquitinated CARD of RIG-I bind to IPS-1 (located on the outer membrane of mitochondria). The CARD of RIG-I undergoes ubiquitination by TRIM25. IPS-1 then interacts with TRADD and forms a complex with FADD and caspase 8/10 to activate NF-κB through the IKK complex. TRADD also interacts with TRAF3 and activates TBK1/IKKi, which phosphorylates IRF3 and IRF7 to induce the transcription of type I IFNs. The mitochondrial NLRX1 inhibits IPS-1-mediated signalling. Mitochondrially localized STING interacts with RIG-I and IPS-1 and activates NF-κB and IRFs.

TRAF3, an E3 ubiquitin ligase that polyubiquitinates through its C-terminal TRAF domain, was shown to interact with IPS-1 and activates TBK1 and IKKi [99,100,148]. Recently, a de-ubiquitinase enzymatic protein known as DUBA (de-ubiquitinating enzyme A) was reported to deubiquitinate TRAF3 and inhibit the RLR-mediated signalling pathway [149].

RLR-mediated NF-κB activation is achieved via the FADD (Fas-associated death domain) protein, which interacts with caspase 8 and caspase 10 and forms a complex with IPS-1 [139,150]. The TNFR-I (TNF receptor-I) signalling adaptor TRADD (TNF-receptor-associated DD), an adaptor in the TNFR-I signalling pathway, has been suggested to be involved in RLR signalling. The engagement of RLRs by viruses leads to the formation of a molecular complex that consists of TRADD, FADD and RIP1. This complex interacts with IPS-1 and activates IRF3 and NF-κB [151].

The ER-localized STING [stimulator of interferon genes, also known as MITA (mediator of IRF3 activation)] protein was recently identified and shown to be involved in host defence against RNA virus. Knockdown of STING impaired IFN-β production by poly(I-C) transfection. The replication of RNA viruses is higher in STING-deficient fibroblast cells than in WT cells. In addition, the production of IFN-β was also reduced in STING-deficient fibroblast cells. However, STING-deficient bone-marrow-derived macrophages and DCs show replication of virus comparable with that shown by WT cells, suggesting a cell-type-specific role of STING [152,153].

Autophagy is an essential biological process that maintains cellular homoeostasis, development, differentiation and tissue remodelling. Recent studies have highlighted the importance of autophagy in innate immunity. Recently it was shown that IPS-1 and RIG-I were associated with the Atg5–Atg12 complex, which is an essential component for autophagy. Mouse embryonic fibroblasts deficient in Atg5 and Atg12 show increased levels of type I IFN production in response to VSV infection [154]. This observation suggests that autophagy is important in the negative regulation of the RLR signalling pathway. However, it has been shown that autophagy plays an opposite role in pDCs. In pDCs, TLR7 recognizes ssRNA in the endolysosome, but it also recognizes replicating VSV. Atg5-deficient pDCs show reduced IFN-α production after VSV infection, suggesting that the autophagosome is formed after VSV infection and contains viral RNA, and this autophagosome traffics to the lysosome, where it forms a complex with the autophagolysosome after fusion with the lysosome. In the autophagolysosome, TLR7 recognizes viral RNA for the production of IFN-α [155].

RECOGNITION OF DNA BY CYTOSOLIC RECEPTOR

Bacterial and viral dsDNA are immunostimulatory components that activate various cell types to induce type I IFNs and inflammatory cytokines through cytosolic DNA sensors. Cytosolic recognition of dsDNA induces TBK1/IKKi-dependent type I IFNs and NF-κB-dependent inflammatory cytokines [156,157] (Figure 5). DAI (DNA-dependent activator of IRFs) has been reported to be a cytosolic sensor for DNA [158]. However, DAI-deficient cells do not show impaired cytokine production, suggesting that DAI is not essential for the recognition of DNA [159]. Recently, we have shown that a DNA vaccine that consists of plasmid DNA and has inherited properties of adjuvant induces innate and adaptive immunity, such as antigen-specific antibody production and CD4 and CD8 T-cell responses, through TBK1 but not TLR9, MyD88 and DAI. This suggests that the DNA-induced adjuvant effects are TLR- and DAI-independent phenomena and these effects may depend on an unknown DNA sensor that signals through TBK1 [159].

Recognition of DNA and DNA viruses by DNA sensors

Figure 5
Recognition of DNA and DNA viruses by DNA sensors

An unknown cytosolic DNA sensor or DAI activates NF-κB through activation of the IKK complex and IRF3 and IRF7 through TBK1/IKKi. ER-localized STING induces the activation of NF-κB and IRFs. DNA virus infection and introduction of dsDNA activates the inflammasome consisting of AIM2/ASC and NALP3/ASC respectively. The inflammasome converts inactive pro-caspase 1 into active caspase 1 for the maturation and production of IL-1β. Adenovirus infection directly or indirectly activates the NALP3 inflammasome.

Figure 5
Recognition of DNA and DNA viruses by DNA sensors

An unknown cytosolic DNA sensor or DAI activates NF-κB through activation of the IKK complex and IRF3 and IRF7 through TBK1/IKKi. ER-localized STING induces the activation of NF-κB and IRFs. DNA virus infection and introduction of dsDNA activates the inflammasome consisting of AIM2/ASC and NALP3/ASC respectively. The inflammasome converts inactive pro-caspase 1 into active caspase 1 for the maturation and production of IL-1β. Adenovirus infection directly or indirectly activates the NALP3 inflammasome.

Recently, STING has been shown to be involved in the recognition of dsDNA. STING was shown to play a pivotal role in type I IFN production by dsDNA when introduced into the cytosol. Furthermore, infection with a DNA virus such as HSV-1, and Listeria monocytogenes, organisms which are known to introduce DNA into the cytosol during infection, shows a reduced type I IFN production in STING-deficient cells. This suggests that STING plays an important role in DNA sensor signalling pathways [152,153].

NOD-LIKE RECEPTORS

The NLR family of proteins are cytosolic, intracellular PRRs that recognize PAMPs and endogenous ligands. The recognition of ligands induces a signalling cascade leading to activation of NF-κB, or a cytoplasmic multiprotein complex known as the inflammasome, to produce inflammatory cytokines [1,11,1213,160,161]. In addition, NLRs are also involved in the signalling for cell death after microbial infection [162]. The NLR family comprises 23 proteins in humans and 34 proteins in mice [163]. However, the function of most of the NLR proteins is poorly understood. These proteins have a trimodular structure and consist of the following domains. The C-terminal domain consists of tandem repeats of LRR, which are essential for sensing or recognition of the microbial components. A centrally located nucleotide binding NOD domain is essential for self-oligomerization and formation of a complex for the activation and recruitment of downstream signalling proteins. The variable N-terminal domains are defined by CARD, DED (death effector domain), PYD (pyrin domain) or BIR (baculovirus inhibitor of apoptosis protein repeat) domain [163]. These domains are essential for downstream signal transduction through homotypic protein–protein interactions. Mutations in these proteins were reported to be associated with chronic inflammatory diseases such as familial cold autoinflammatory syndromes (familial cold urticaria) [164,165], Muckle-well (or urticaria–deafness–amyloidosis) syndrome and Crohn's disease [166].

NOD1 AND NOD2

NOD1 (also known as CARD4) recognizes a distinct substructure of PGN (peptidoglycan), namely iE-DAP (γ-D-glutamyl-m-diaminopimelic acid, a dipeptide), which is present in Gram-negative and Gram-positive bacteria such as Bacillus subtilis and L. monocytogenes [167,168]. NOD2 (CARD15) recognizes MDP (muramyl dipeptide), the largest component of PGN motif, which is also present in Gram-negative and Gram-positive bacteria [169].

Upon stimulation with these ligands, NOD1 and NOD2 interact with a CARD domain-containing serine/threonine kinase known as CARDIAK [CARD-containing IL-1β-converting-enzyme-associated kinase, also known as RICK (RIP-like interacting caspase-like apoptosis-regulatory protein kinase) and RIP2] [170,171] and induces antimicrobial peptides [172] and inflammatory cytokines through activation of MAPKs [173] and NF-κB. MAPKs are activated through another CARD-containing protein known as CARD9 [174] (Figure 6). Ex vivo studies showed that various pathogenic bacteria, such as E. coli [175], Shigella flexneri [168], Pseudomonas aeruginosa [176], Chlamydia species [177,178179], Campylobacter jejuni [180] and Haemophilus influenza [181] are sensed by NOD1 and Strep. pneumonia [182] and M. tuberculosis [183] are sensed by NOD2. L. monocytogenes has been reported to be sensed by both NOD1 and NOD2 [184,185]. In vivo, it has been shown that NOD1 and NOD2-deficient mice are susceptible to L. monocytogenes and H. pylori respectively [185,186].

NLR signalling pathway

Figure 6
NLR signalling pathway

NOD1 and NOD2 sense various PAMPs of pathogenic bacteria in the cytoplasm or PAMPs that are transported through the type III or type IV secretion systems. Upon recognition of PAMPs, these sensors undergo for self-oligomerization and formation of a complex that triggers the association of CARDIAK, which in turn activates NF-κB. NOD1 and NOD2 also activate the MAPK signalling pathway through CARD9.

Figure 6
NLR signalling pathway

NOD1 and NOD2 sense various PAMPs of pathogenic bacteria in the cytoplasm or PAMPs that are transported through the type III or type IV secretion systems. Upon recognition of PAMPs, these sensors undergo for self-oligomerization and formation of a complex that triggers the association of CARDIAK, which in turn activates NF-κB. NOD1 and NOD2 also activate the MAPK signalling pathway through CARD9.

The inflammasome

Pathogen infection into the host results in the production of various inflammatory cytokines. The IL-1 family of cytokines, including IL-1β, IL-18 and IL-33, are key cytokines that regulate various components of innate and adaptive immunity. The production of these cytokines is regulated by two signals in the innate immune cells (e.g. macrophages). The first signal is transcriptional and translational up-regulation of pro-forms of the cytokine (pro-IL-1β, pro-IL-18) in response to various TLR, NLR and RLR agonists. The second signal is the processing of the pro-form of these cytokines to the mature, secretary form of the cytokines by the inflammasome. Depending on the NLR proteins, the inflammasome is categorized into three types such as NALP3 [NACHT (NTPase-domain named after NAIP, CIITA, HET-E and TP1)–LRR-PYD–containing protein 3, also known as NLRP3, CIAS1 (cold-induced autoinflammatory syndrome 1) and cryopyrin] inflammasome, the IPAF [IL-1β-converting-enzyme protease-activating factor, also known as the NLRC4 (NLR family, CARD domain containing 4)] and CLAN (CARD LRR- and NACHT-domain-containing protein) inflammasome and the NALP1 (also known as NLRP1) inflammasome (Figure 7).

Activation of the inflammasome

Figure 7
Activation of the inflammasome

The inflammasome is activated in two steps. The first step is transcriptional and translational up-regulation of pro-forms of the cytokine (pro-IL-1β, pro-IL-18) in response to various TLR, NLR and RLR agonists through activation of NF-κB. In the second step, the inactive form of the cytokines is converted into a biologically active form by the inflammasome. The ligands (described in the text) directly and indirectly (through an unknown sensor) induce the formation of various inflammasomes such as the NALP3 inflammasome, the IPAF inflammasome or the NALP1 inflammasome. In addition to ASC, the NALP3 inflammasome contains CARDINAL protein (the domain arrangement of each component is shown in the box labelled ‘Components of inflammasome’. The inflammasome converts inactive pro-caspase 1 into active caspase 1, which induces cell death (in the case of NALP1 inflammasome) and/or converts pro-cytokines (inactive) into bioactive secretory cytokines. The NALP1 protein interacts with anti-apoptotic proteins such as Bcl-2 and Bcl-XL and inhibits caspase-1-dependent cell death and production of IL-1β and IL-18.

Figure 7
Activation of the inflammasome

The inflammasome is activated in two steps. The first step is transcriptional and translational up-regulation of pro-forms of the cytokine (pro-IL-1β, pro-IL-18) in response to various TLR, NLR and RLR agonists through activation of NF-κB. In the second step, the inactive form of the cytokines is converted into a biologically active form by the inflammasome. The ligands (described in the text) directly and indirectly (through an unknown sensor) induce the formation of various inflammasomes such as the NALP3 inflammasome, the IPAF inflammasome or the NALP1 inflammasome. In addition to ASC, the NALP3 inflammasome contains CARDINAL protein (the domain arrangement of each component is shown in the box labelled ‘Components of inflammasome’. The inflammasome converts inactive pro-caspase 1 into active caspase 1, which induces cell death (in the case of NALP1 inflammasome) and/or converts pro-cytokines (inactive) into bioactive secretory cytokines. The NALP1 protein interacts with anti-apoptotic proteins such as Bcl-2 and Bcl-XL and inhibits caspase-1-dependent cell death and production of IL-1β and IL-18.

NALP3 inflammasome

The NALP3 inflammasome is activated by various exogenous and host endogenous ligands. Exogenous ligands include microbial ligands such as MDP, bacterial and viral RNA, toxins such as nigericin, maitotoxin, environmental pollutants such as asbestos and silica [187] and vaccine adjuvant alum (aluminium salts) [188,189]. Host endogenous ligands include MSU (monosodium urate), calcium pyrophosphate dehydrate, amyloid-β fibrillar peptide and ATP. In addition, the NALP3 inflammasome is also activated by UV light and skin irritants such as picryl chloride and 2,4-dinitrofluorobenzene. The NALP3 inflammasome consists of NALP3, CARDINAL (CARD inhibitor of NF-κB-activating ligands), ASC (apoptosis-associated speck-like protein containing a CARD) and caspase 1, which process cytosolic pro-IL-1β to bioactive secretory IL-1β [187].

Activation of the inflammasome leads to the production of IL-1β, which may play an important role in clearing pathogens from the host. A recent study has shown that the NALP3 inflammasome is essential for alum-induced adjuvant effects such as antibody production to antigens and Th2-mediated inflammation [189]. However, there is another study showing that the NALP3 inflammasome is dispensable for the adjuvant effects, but indispensible for IL-1β production [190]. There are several possible differences among these studies, such as preparation of mixture of antigen and alum before immunization, the dose of antigen or adjuvant, the purity of antigen (some antigen has impurity of immunomodulatory substances), and the route and protocol of immunization. Therefore it is almost impossible to evaluate the data from two different laboratories. Furthermore, the differences in results could be due to multiple mechanisms of action of alum. Taken together, further studies are needed to conclude the involvement of NALP3 inflammasome in adjuvant effects of alum. It has been suggested that activation of the inflammasome by the host ligand plays an important role in the pathogenesis of arthritic diseases such as gout, pseudogout [187] and Alzheimer's disease [191]. The exogenous ligand silica induces NALP3-inflammasome-dependent silicosis [192,193]. These observations suggest that the NALP3 inflammasome plays a pivotal role in the activation of innate immune responses for host defence and is a mediator for the pathogenesis of various diseases.

Recently, the introduction of bacterial, viral and host dsDNA into the cytosol of cells has been shown to induce the production of IL-1β, which requires the inflammasome components ASC and caspase 1, but not NALP3. However, the introduction of adenoviral DNA showed that IL-1β production depends on NALP3, ASC and caspase 1. AIM2 (absent in melanoma 2) has been shown to recognize dsDNA. AIM2 is a member of the IFI20X (interferon-inducible protein 20X)/IFI16 or PYHIN [PYD and HIN (haematopoietic interferon-inducible) nuclear protein domain family member 1]. It has been shown that the HIN200 domain of AIM2 binds to dsDNA, whereas PYD associates with ASC [194,195,196197] (Figure 5).

The NALP3 inflammasome is activated by numerous ligands; however, it is unknown whether these ligands bind directly to NALP3. Pore-forming toxins such as staphylococcal α-toxin and pneumolysin, K+ ionophores and a low concentration of detergent induce an efflux of K+ to activate the NALP3 inflammasome. In addition, ATP, maitotoxin and nigericin activate hemichannel pannexin-1 and the purinergic receptor P2×7 to induce efflux of K+ and activate the NALP3 inflammasome. Furthermore, ROS (reactive oxygen species) are also reported to activate the NALP3 inflammasome [187]. Two different mechanisms for ROS production have been proposed, including efflux of K+-induced stress to the mitochondria and NADPH oxidase-mediated induction in the phagolysosome. Other mechanisms have also been proposed recently. Phagocytosis of silica crystal and fibrous particles of amyloid-β induce lysosomal destabilization and permeabilization which leads to the release of cathepsin B into the cytosol [191,198]. The released cathepsin B activates the NALP3 inflammasome.

IPAF inflammasome

The IPAF inflammasome is activated by intracellular pathogens such as Salmonella typhimurium [199] and Legionella pneumophila [200]. It was suggested that S. typhimurium and L. pneumophila deliver flagellin to the cytosol via the type III and type IV secretion systems respectively [199,200]. The introduction of recombinant purified flagellin protein into the cytosol also promotes IPAF-dependent caspase 1 activation [201]. Flagellin of Ps. aeruginosa also induces IPAF- and caspase-1-dependent production of IL-1β [202]. In addition to IPAF, NAIP5 (apoptosis inhibitory protein 5, also known as Birc1 (BIR-containing 1)] was reported to be involved in the recognition of L. pneumophila [203,204]. NAIP5 consists of three consecutive repeats of the BIR domain at the N-terminus. Previous studies have indicated that NAIP5 regulates the replication of L. pneumophila via caspase-1-dependent cell death. It has been reported that 35 amino acids from the C-terminus of flagellin and infection with L. pneumophila is sufficient to activate the inflammasome, but is not activated in the absence of NAIP5. In addition, full-length flagellin activates NAIP5-independent, but IPAF-dependent, cell death [205]. These findings suggest that the IPAF and NAIP5 proteins are essential for the flagellin-induced immune response.

NALP1 inflammasome

Anthrax LT (lethal toxin) is a potent toxin of Bacillus anthracis that induces cell death [206]. LT is composed of a protective antigen and a lethal factor. The protective antigen is a receptor-binding protein that creates a pore to deliver the lethal factor into the cytosol of infected cells and induce cell death. It has been shown that the polymorphic gene known as Nlrp1b is responsible for susceptibility to LT [207]. It was also shown that LT-induced macrophage death requires caspase 1, which is activated in susceptible macrophages [207]. Furthermore, the LT of B. anthracis was shown to induce IL-1β, which depends on the NALP1 inflammasome. In addition, it was shown that NOD2 is also required for IL-1β production and NOD2–NALP1 forms a molecular complex during infection [208].

NALP1 is implicated in the association with anti-apoptotic proteins Bcl2 (B-cell lymphoma-2) and Bcl-X(L), which suppress caspase-1 activation, indicating a role of Bcl-2 proteins in the inhibition of LT-induced cytotoxicity [209].

CONCLUSIONS AND FUTURE DIRECTIONS

Although numerous studies have greatly enhanced our understanding of innate immune recognition by TLRs, RLRs, NLRs and unknown PRRs, we still know relatively little about the recognition of the vast array of micro-organisms and the cross-talk among these receptors. Although the cytosolic receptor for DNA, which induces IL-1β production, has been reported, we have not yet characterized the sensors for DNA or DNA viruses that activate IRFs. The function of most of the members of the NLR family in host defence and their ligands are also unidentified. Characterization of these PRRs in innate immunity will further improve our understanding of the complexities of innate immune regulation. In addition, structural studies of PRR–ligand complexes will improve our understanding of innate immunity and facilitate the design of novel drugs that target PRRs.

Abbreviations

     
  • AIM2

    absent in melanoma 2

  •  
  • alum

    aluminium salts

  •  
  • AP-1

    activator protein-1

  •  
  • ASC

    apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain)

  •  
  • Atg

    autophagy-related

  •  
  • Atg16L1

    autophagy-related 16-like 1

  •  
  • Bcl

    B-cell lymphoma

  •  
  • BIR

    baculovirus inhibitor of apoptosis protein repeat

  •  
  • Birc1

    BIR-containing 1

  •  
  • CARD

    caspase recruitment domain

  •  
  • CARDIAK

    CARD-containing IL (interleukin)-1β converting enzyme-associated kinase

  •  
  • Cardif

    CARD adaptor inducing IFN-β

  •  
  • CARDINAL

    CARD inhibitor of nuclear factor-κB-activating ligands

  •  
  • cDC

    conventional dendritic cell

  •  
  • CIAS

    cold-induced autoinflammatory syndrome 1

  •  
  • CLAN

    CARD LRR- and NACHT-domain-containing protein

  •  
  • CLR

    C-type lectin receptor

  •  
  • CTD

    C-terminal domain

  •  
  • DAI

    DNA-dependent activator of IRFs

  •  
  • DAK

    dihydroacetone kinase

  •  
  • DC

    dendritic cell

  •  
  • DED

    death effector domain

  •  
  • ds

    double-stranded

  •  
  • DUBA

    de-ubiquitinating enzyme A

  •  
  • DV

    dengue virus

  •  
  • EDA

    extracellular domain A

  •  
  • EMCV

    encephalomyocarditis virus

  •  
  • ER

    endoplasmic reticulum

  •  
  • ERK

    extracellular-signal-regulated kinase

  •  
  • FADD

    Fas-associated death-domain

  •  
  • GPI

    glycosylphosphatidylinositol

  •  
  • HCV

    hepatitis C virus

  •  
  • HIN

    haematopoietic interferon-inducible

  •  
  • HSE

    herpes simplex virus encephalitis

  •  
  • HSV

    herpes simplex virus

  •  
  • iE-DAP

    γ-D-glutamyl-m-diaminopimelic acid

  •  
  • IFI

    interferon-inducible, IFN, interferon

  •  
  • IκB

    inhibitor of κB

  •  
  • IKK

    IκB kinase

  •  
  • IL

    interleukin

  •  
  • iNOS

    inducible NO synthase

  •  
  • IPAF

    IL-1β converting enzyme protease activating factor

  •  
  • IPS-1

    IFN-β promoter stimulator-1

  •  
  • IRAK

    IL-1 receptor-associated kinase

  •  
  • IRF

    IFN regulatory factor

  •  
  • ISRE

    IFN-stimulated response element

  •  
  • IV

    influenza virus

  •  
  • JEV

    Japanese-encephalitis virus

  •  
  • JNK

    c-jun N-terminal kinase

  •  
  • LBP

    LPS-binding protein

  •  
  • LCMV

    lymphocytic choriomeningitis virus

  •  
  • Lgp2

    Laboratory of Genetics and Physiology 2

  •  
  • LPDC

    lamina propria DC

  •  
  • LPS

    lipopolysaccharide

  •  
  • LRR

    leucine-rich repeat

  •  
  • LT

    lethal toxin

  •  
  • LTA

    lipoteichoic acid

  •  
  • MAL

    MyD88-adaptor-like

  •  
  • MALP-2

    macrophage-activating lipopeptide

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MAVS

    mitochondrial antiviral signalling

  •  
  • MCMV

    murine cytomegalovirus

  •  
  • MD2

    myeloid differentiation protein-2

  •  
  • Mda5

    melanoma differentiation-associated gene 5

  •  
  • MDP

    muramyl dipeptide

  •  
  • MITA

    mediator of IRF3 activation

  •  
  • MMTV

    mouse mammary tumour virus

  •  
  • MSU

    monosodium urate

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • MyD88

    myeloid differentiation primary response gene 88

  •  
  • NACHT

    NTPase-domain named after NAIP, CIITA, HET-E and TP1

  •  
  • NAIP

    NLR family, apoptosis inhibitory protein

  •  
  • NAIP5

    neuronal apoptosis inhibitor protein 5

  •  
  • NAK

    NF-κB activating kinase

  •  
  • NALP

    NACHT/LRR/PYD-containing protein

  •  
  • NAP

    NAK-associated protein

  •  
  • NDV

    Newcastle-disease virus

  •  
  • NEMO

    NF-κB essential modifier

  •  
  • NF-κB

    nuclear factor κB

  •  
  • NK

    natural killer

  •  
  • NLR

    Nod-like receptor

  •  
  • NLRC

    NLR family CARD-domain-containing

  •  
  • NLRP

    NLR family pyrin-domain-containing

  •  
  • NOD

    nucleotide-binding oligomerization domain

  •  
  • ODN

    oligodeoxynucleotide

  •  
  • PAMP

    pathogen-associated molecular pattern

  •  
  • pDCs

    plasmacytoid dendritic cells

  •  
  • PGN

    peptidoglycan

  •  
  • Phox

    phagocyte oxidase

  •  
  • PKR

    protein kinase receptor

  •  
  • PRR

    pattern-recognition receptor

  •  
  • PYCARD

    PYD- and CARD-domain-containing

  •  
  • PYD

    pyrin domain

  •  
  • PYHIN

    PYD and HIN domain family member 1

  •  
  • PYPAF

    PYD-containing APAF-1 (apoptotic peptidase activating factor 1)-like protein

  •  
  • RD

    repressor domain

  •  
  • RICK

    RIP-like interacting caspase-like apoptosis-regulatory protein kinase

  •  
  • RIG-I

    retinoic acid-inducible gene-I

  •  
  • RIP

    receptor-interacting protein

  •  
  • RLR

    RIG-I-like receptor

  •  
  • RNF

    ring finger

  •  
  • ROS

    reactive oxygen species

  •  
  • RSV

    respiratory syncytial virus

  •  
  • SeV

    Sendai virus

  •  
  • SINTBAD

    similar to NAP1 TBK1 adaptor

  •  
  • SNP

    single-nucleotide polymorphism

  •  
  • ss

    single-stranded

  •  
  • STING

    stimulator of interferon genes

  •  
  • T2K

    TRAF2-associated kinase

  •  
  • TAB

    TAK1-binding protein

  •  
  • TAK1

    transforming-growth-factor-β-activated kinase 1

  •  
  • TANK

    TRAF family member associated NF-κB activator

  •  
  • TBK1

    TANK-binding kinase 1

  •  
  • Th

    T-helper

  •  
  • TICAM

    TIR-domain-containing adaptor molecule

  •  
  • TIR

    Toll/IL-1 receptor

  •  
  • TIRAP

    TIR-containing adaptor protein

  •  
  • TLR

    Toll-like receptor

  •  
  • TNF

    tumour necrosis factor

  •  
  • TNFR

    TNF receptor

  •  
  • TRADD

    TNF-receptor-associated DD

  •  
  • TRAF

    TNF-receptor-associated factor

  •  
  • TRAM

    TRIF-related adaptor molecule

  •  
  • TRIF

    TIR-containing adaptor inducing IFN-β

  •  
  • TRIM

    tripartite motif

  •  
  • UBC

    ubiquitin C

  •  
  • UEV

    ubiquitin-conjugating enzyme variant

  •  
  • VISA

    virus-induced signalling adaptor

  •  
  • VSV

    vesicular-stomatitis virus

  •  
  • WNV

    West Nile virus

  •  
  • WT

    wild-type

We thank the members of our laboratory for insightful discussions and apologize to those authors whose work could not be included in this review owing to space limitations.

FUNDING

This work was supported by the Japan Society for the Promotion of Science [grant number PO8123 (postdoctoral fellowship to H. K.)].

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