Abstract
Many of the ligands for Toll-like receptors (TLRs) are unique to microorganisms, such that receptor activation unequivocally indicates the presence of something foreign. However, a subset of TLRs recognizes nucleic acids, which are present in both the host and foreign microorganisms. This specificity enables broad recognition by virtue of the ubiquity of nucleic acids but also introduces the possibility of self-recognition and autoinflammatory or autoimmune disease. Defining the regulatory mechanisms required to ensure proper discrimination between foreign and self-nucleic acids by TLRs is an area of intense research. Progress over the past decade has revealed a complex array of regulatory mechanisms that ensure maintenance of this delicate balance. These regulatory mechanisms can be divided into a conceptual framework with four categories: compartmentalization, ligand availability, receptor expression and signal transduction. In this Review, we discuss our current understanding of each of these layers of regulation.
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Acknowledgements
Research on nucleic acid sensing by TLRs in the Barton laboratory is supported by funding from the US National Institutes of Health (AI072429). K.P. is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute. V.E.R. is supported by the National Science Foundation Graduate Research Fellowship Program under grant no. DGE 1752814.
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Glossary
- CpG motifs
-
Short single-stranded oligodeoxynucleotides containing unmethylated CpG motifs function as Toll-like receptor 9 (TLR9) agonists. Different classes of CpG oligodeoxynucleotide are given letter designations (for example, CpG-A, CpG-B and CpG-C) based on the distinct responses they elicit.
- Systemic lupus erythematosus
-
(SLE). A chronic autoimmune disease characterized by the production of antinuclear autoantibodies and often associated with production of type I interferon. The pathology of SLE can affect joints, skin, brain, lungs, kidneys and blood vessels.
- Psoriasis
-
A chronic autoimmune disease characterized by inflammation of the skin, leading to raised patches of dry and scaly skin.
- Cytosolic sensors of nucleic acids
-
Innate immune sensors of infection that detect nucleic acids and reside in the cytosol. Examples include the cGAS–STING pathway and AIM2, which detect DNA, and RIG-I and MDA5, which detect RNA.
- Apoptotic cell microparticles
-
Small membrane-coated particles released from apoptotic cells that contain genomic DNA and chromatin, as well as RNA.
- cGAS–STING pathway
-
An innate immune sensing pathway that detects the presence of cytosolic double-stranded DNA and triggers the transcription of type I interferon and other genes involved in the host response.
- Neutrophil extracellular traps
-
Web-like structures of DNA released into the extracellular space by neutrophils. Neutrophil extracellular traps can trap microorganisms and prevent their dissemination, but in some contexts, they can be a source of self-nucleic acids that drive autoimmune diseases, such as systemic lupus erythematosus and psoriasis.
- Suboptimal codons
-
Codons that are used at a lower than expected frequency in a given genome. Such codons often result in less efficient translation, which is thought to be owing, at least in part, to the limited availability of corresponding transfer RNAs.
- Myddosome
-
A multiprotein signalling complex consisting of the adaptor protein MYD88 and members of the IL-1 receptor-associated kinase (IRAK) family that assembles upon activation of all Toll-like receptors (TLRs), except for TLR3.
- Syntenin-1
-
A PDZ domain-containing adaptor protein that has been implicated in the biogenesis of exosomes and that supports intraluminal budding and delivery of cargo into intraluminal vesicles.
- Multivesicular bodies
-
Specialized organelles within the endolysosomal network that are characterized by the presence of vesicles within their lumen. These intraluminal vesicles form by budding from the limiting membrane into the lumen. Sorting of cargo into multivesicular bodies is a common mechanism by which receptor signalling is terminated.
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Lind, N.A., Rael, V.E., Pestal, K. et al. Regulation of the nucleic acid-sensing Toll-like receptors. Nat Rev Immunol 22, 224–235 (2022). https://doi.org/10.1038/s41577-021-00577-0
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DOI: https://doi.org/10.1038/s41577-021-00577-0