Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity

Abstract

Host cells trigger signals for innate immune responses upon recognition of conserved structures in microbial pathogens. Nucleic acids, which are critical components for inheriting genetic information in all species including pathogens, are key structures sensed by the innate immune system. The corresponding receptors for foreign nucleic acids include members of Toll-like receptors, RIG-I-like receptors, and intracellular DNA sensors. While nucleic acid recognition by these receptors is required for host defense against the pathogen, there is a potential risk to the host of self-nucleic acids recognition, thus precipitating autoimmune and autoinflammatory diseases. In this review, we discuss the roles of nucleic acid-sensing receptors in guarding against pathogen invasion, discriminating between self and non-self, and contributing to autoimmunity and autoinflammatory diseases.

Figure 1

Overview of signaling pathway in nucleic acid‐sensing TLRs. Nucleic acid‐sensing TLR3, TLR7, TLR8, and TLR9 are localized in the endolysosome and recognize nucleic acids that enter the endolysosome. TLR3 signals through TRIF, whereas TLR7, TLR8, and TLR9 signal through MyD88. Each adapter molecule induces complex formation of specific downstream signaling proteins. TRIF recruits TRAF6, TRAF3, TRADD, RIP1, and TAK1, and MyD88 recruits IRAK2, IRAK4, TRAF6, and TAK1. TAK1 induces activation of canonical IKKα/β complex, resulting in NF‐κB activation. TRAF3 is recruited to TRIF and leads to activation of TBK1 and IKKι to phosphorylate IRF3.

Figure 2

Signaling scheme of RLRs and cytosolic DNA sensors. RNA from RNA viruses is recognized by RIG‐I and MDA5. RIG‐I and MDA5 form a complex with an adapter IPS‐1, which is located in the mitochondria. IPS‐1 induces the assembly of downstream signaling proteins: TRAF3/6, caspase‐8/10, RIP1, FADD, and TRADD. This complex further induces activation of NF‐κB and IRF3 through IKKα/β and TBK1/IKKι, leading to production of inflammatory cytokines and type I IFNs, respectively. DNA from DNA viruses or bacteria causes cytokine production via several pathways. AIM2 forms an inflammasome along with ASC and Caspase‐1 and produces IL‐1β and IL‐18. Poly (dA:dT) that is transcribed to RNA via RNA pol II is recognized by RIG‐I. DAI and IFI16 may signal through STING, whereas DHX9 and DHX36 signal through MyD88. STING is localized in the ER or mitochondria and may change distribution during activation, leading to TBK1/IKKι‐dependent IRF3 activation.

Figure 3

Self‐nucleic acid recognition mechanisms and degradation of DNA. Self‐nucleic acids, which are produced from necrotic or apoptotic cells, are internalized via several pathways and induce innate immune responses. Extracellular DNA is degraded by DNase I, but some of this escapes from degradation by binding to intermediate proteins, such as autoantibodies, LL37, or HMGB1. DNA–protein complexes facilitate internalization through the endocytosis pathway by binding to specific mediators. DNase II plays a role similar to DNase I after self‐DNA internalization or degradation of DNA derived from phagocytosed apoptotic cells in the macrophage. DNase III degrades intracellular DNA derived from the retro element from genomic DNA, which is likely to prevent activation of the cytosolic DNA sensor.