Extracellular RNA Sensing by Pattern Recognition Receptors

Abstract

RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated. All of the Toll-like receptors that recognize RNA are localized to endosomes/lysosomes, which require internalization of RNA for sensing through an endocytic pathway. RIG-I-like receptors sense RNA in cytosol. These receptors are expressed in a cell type-specific fashion, enabling sensing of RNA for a wide range of microbial invasions. At the same time, both endosomal and cytoplasmic receptors have strategies to respond only to RNA of pathogenic microorganisms or dying cells. RNA are potential vaccine adjuvants for immune enhancement against cancer and provide a benefit for vaccinations. Understanding the detailed molecular mechanisms of the RNA-sensing system will help us to broaden the clinical utility of RNA adjuvants for patients with incurable diseases.

Interspecies Communication in Holobionts by Non-Coding RNA Exchange

“…The role of host specific families of ncRNAs, such as miRNAs, in reshaping the immune response against pathogens has been reviewed elsewhere [130]. Surface pattern recognition receptors (PRRs), such as the Toll-like receptors (TLRs), can recognize structural features of bacterial and fungal pathogens, which include single-and double-stranded RNAs and can trigger a cascade of signals that often involves the production of cytokines [131]. Some bacterial pathogens can hijack the defensive system by inducing the expression of specific miRNAs that can extend their survival or downregulate the production of cytokines.…”

Mitochondrial dsRNAs activate PKR and TLR3 to promote chondrocyte degeneration in osteoarthritis

“…They are abundantly present in DNA and positive-sense single-stranded RNA viruses 24 . When expressed in mammalian cells, these dsRNAs are recognized by PRRs, which leads to suppression of global translation, induction of interferons and proinflammatory cytokines, and eventually, cell death 25 . However, increasing evidence suggests that human cells naturally encode cellular dsRNAs that can regulate antiviral machinery.…”

Mitochondrial Double‐Stranded RNA in Exosome Promotes Interleukin‐17 Production Through Toll‐Like Receptor 3 in Alcohol‐associated Liver Injury

“…Currently, three types of pattern recognition receptors, including retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and TLR3, are thought to play key roles in the host defense against dsRNA viral infection. (21,22) Extracellular dsRNAs are internalized by cells through clathrin-dependent endocytosis, in which TLR3 recognizes dsRNA (>40 base pairs [bp]) in the endosome or internalized dsRNA exits from the endosome to the cytosol through a mammalian dsRNA transporter: systemic RNA interference defective protein-1, transmembrane family member 2. (22) In the cytoplasm, RIG-I recognizes short dsRNA with a 5′-triphosphate end generated by viral polymerase, whereas MDA5 detects long dsRNA (>1,000 bp).…”

“…(21,22) Extracellular dsRNAs are internalized by cells through clathrin-dependent endocytosis, in which TLR3 recognizes dsRNA (>40 base pairs [bp]) in the endosome or internalized dsRNA exits from the endosome to the cytosol through a mammalian dsRNA transporter: systemic RNA interference defective protein-1, transmembrane family member 2. (22) In the cytoplasm, RIG-I recognizes short dsRNA with a 5′-triphosphate end generated by viral polymerase, whereas MDA5 detects long dsRNA (>1,000 bp). (21,22) Although the activation of RNA sensors is strictly regulated to avoid autoimmunity, various self-RNAs, including mtdsRNA, mRNA, and noncoding RNA, activate MDA5 and TLR3.…”