Innate immune responses are initiated by pattern recognition receptors, which recognize specific structures of microorganisms. Among them, toll-like receptors (TLRs) are capable of sensing organisms ranging from viruses to bacteria, fungi, and protozoa and play major roles in innate immunity. TLR activation controls complex gene expression networks that regulate the magnitude and duration of the immune reaction. Autophagy, a bulk degradation system that delivers cytoplasmic constituents in the lysosome, controls degradation of long-lived proteins, insoluble protein aggregates, and invading pathogens. We recently generated mutant mice lacking Atg16L1, an autophagy-related gene that is implicated in Crohn's disease, and thereby examined its role in TLR-mediated inflammatory response. Atg16L1 was indispensable for the formation of autophagosomes and suppression of endotoxin-induced interleukin (IL)-1 production, suggesting that it is responsible for the control of endotoxin-mediated inflammatory responses. Because TLR ligands have been identified and TLR signaling pathways clarified, we are now looking at the effector phase of TLR responses. We are starting to generate knockout (KO) mice of the genes that are induced in response to TLR stimulation, but whose functions are unknown. Among them, we recently identified a novel gene, Zc3h12a, encoding a nuclease involved in destabilization of IL-6 and IL-12 messenger RNAs. KO mice lacking this gene developed spontaneous autoimmune diseases accompanied by splenomegaly and lymphadenopathy. This review describes the phenotypes of our different KO mice models and the role of various molecules in TLR responses.
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Toll receptors in insects, mammals and plants are key players that sense the invasion of pathogens. Toll-like receptors (TLRs) in mammals have been established to detect specific components of bacterial and fungal pathogens. Furthermore, recent evidence indicates that TLRs are involved in the recognition of viral invasion. Signalling pathways via TLRs originate from the conserved Toll/IL-1 receptor (TIR) domain. The TIR domain-containing MyD88 acts as a common adaptor that induces inflammatory cytokines; however, there exists a MyD88-independent pathway that induces type I IFNs in TLR4 and TLR3 signalling. Another TIR domain-containing adaptor, TIRAP/Mal has recently been shown to mediate the MyD88-dependent activation in the TLR4 and TLR2 signalling pathway. Thus, individual TLRs may have their own signalling systems that characterize their specific activities.
