Toll-Like Receptor 3: Involvement with Exogenous and Endogenous RNA

Abstract

The recognition of pathogens is assigned to an evolutionarily conserved family of receptors, the Toll-like receptors (TLRs). The investigation of RNA-based immunology has been reinvigorated with the observation that TLR3s interact with RNA (dsRNA of viral origin, poly (I:C) and endogenous RNA). Many RNAs, therefore, join the list of endogenous ligands for TLRs. The further finding that nucleoside modification alters RNA-mediated TLR signaling presents a mechanism for the long-observed differences in immunogenicity. The involvement of RNA modification in the pathogenesis of diseases, and its implications in the therapeutics, are still being studied, and will have important implications in the future.

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“…Mammalian TLRs also respond to host-derived molecules that are released from injured tissues and cells, termed damage associated molecular patterns (DAMPs) (33). TLR-ligand binding plays a key role in innate immunity and subsequent acquired immunity against microbial infection or tissue injury (34).…”

“…Dimerization of TLR3 is required for ligand binding, and dsRNA molecules must be at least 40 to 50 bp in length in order to induce TLR3 signaling (49). TLR3 was originally identified to recognize a synthetic analog of dsRNA, the polyinosinic:polyribocytidylic acid [poly(I:C)], which was found to be the most potent IFN inducer (34). TLR3 also recognizes genomic RNA from dsRNA viruses (including reoviruses) and dsRNA produced during replication of single-stranded RNA viruses (such as influenza A virus, encephalomyocarditis virus, and West Nile virus) and double-stranded DNA viruses (herpes simplex virus and murine cytomegalovirus) (40,50).…”

“…Cell-surface TLRs, including TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10, are essential to recognizing bacterial cell wall components, bacterial flagellin, viral particles, and other unidentified pathogenic components. TLR3, TLR7, TLR8, and TLR9 are localized in endosomes, and their ligands, mainly bacterial or viral nucleic acids, require internalization to the endosome before signaling is possible (Table 1) (10,34,40).…”

“…In addition to TLR3, dsRNA is recognized by the RLHs, RIG-I and melanoma differentiation-associated gene 5 (MDA5 or IFIH1). TLR3 and RIG-I/MDA5 differ in their cellular location and ligand specificities, and induce antiviral responses via different signaling pathways (34).…”

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“…22 In another set of experiments, a member of the HSP70 family, HSP70-like protein 1, was shown to activate DCs to immunostimulatory cells via interaction with TLR4. 23 In addition, class I DAMPs also may include nucleic acids (probably predominantly in their oxidized form) such as endogenous double-stranded RNA (dsRNA) 24,25 and double-stranded DNA (dsDNA) (including mitochondrial DNA) that reportedly are released from injury-induced dying cells. [26][27][28] In fact, at present, there is an emerging interest in understanding the mechanisms by which the innate immune system can detect nucleic acids as DAMPs.…”