Journal
CELLULAR & MOLECULAR IMMUNOLOGY
Volume 18, Issue 5, Pages 1235-1248Publisher
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/s41423-021-00668-x
Keywords
cGAS; miR-23a; miR-23b; DNA virus; Innate immunity; Autoimmune disease
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Funding
- National Natural Science Foundation of China [31801076]
- National Key R&D Program of China [2016YFA0501800]
- Natural Science Foundation of Jiangsu Province [BK20180555]
- China Postdoctoral Science Foundation [2018M630641]
- Open Project of State Key Laboratory of Natural Medicines [SKLNMZZCX201802]
- Double First-Class Project of China Pharmaceutical University [CPU2018GF10]
- Jiangsu Innovative and Entrepreneurial Talents Program
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The study reveals that during HSV-1 infection, miR-23a and miR-23b directly regulate cGAS expression through interaction with lncRNA Oasl2-209, and in the autoimmune disease model, miR-23a/b can mitigate self DNA-induced autoinflammatory responses.
Cyclic GMP-AMP synthase (cGAS), a key sensor of intracellular DNA, is essential for eliciting innate immunity against infection, whereas aberrant activation of cGAS by endogenous DNA promotes severe autoimmune diseases. However, it is largely unknown how cGAS expression is regulated during pathogen infection and autoimmunity. Here, we report that during herpes simplex virus type 1 (HSV-1) infection, two microRNAs (miR-23a and miR-23b) whose levels significantly decrease due to their interaction with the lncRNA Oasl2-209 directly regulate the expression of cGAS. Overexpression of miR-23a/b markedly dampens cytosolic DNA-induced innate immune responses, whereas inhibition of miR-23a/b enhances these responses. Mice treated with miR-23a/b agomirs exhibit increased susceptibility to HSV-1 infection. Moreover, cGAS is significantly upregulated in the Trex1(-/-) mouse autoimmune disease model. Administration of miR-23a/b blunts self DNA-induced autoinflammatory responses in Trex1(-/-) mice. Collectively, our study not only reveals a novel regulatory mechanism of cGAS expression by miRNAs but also identifies a potential therapy for cGAS-related autoimmune diseases.
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