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J Immunol. 2016 Feb 1;196(3):1317-26. doi: 10.4049/jimmunol.1502134. Epub 2015 Dec 23.

Type I IFN-Inducible Downregulation of MicroRNA-27a Feedback Inhibits Antiviral Innate Response by Upregulating Siglec1/TRIM27.

Author information

1
National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; and.
2
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China caoxt@immunol.org houjinsmmu@126.com.
3
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
4
National Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; and National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China caoxt@immunol.org houjinsmmu@126.com.

Abstract

Upon recognition of viral components by pattern recognition receptors, including TLRs and retinoic acid-inducible gene I-like helicases, cells are activated to produce type I IFN, which plays key roles in host antiviral innate immune response. However, excessive IFN production may induce immune disorders, and the mechanisms responsible for the regulation of type I IFN production have attracted much attention. Furthermore, type I IFN activates the downstream IFN/JAK/STAT pathway to modulate expression of a set of genes against viral infection, but whether these genes can feedback regulate type I IFN production is poorly understood. In this study, by screening the microRNAs modulated by viral infection in macrophages, we identified that microRNA (miR)-27a was significantly downregulated via the IFN/JAK/STAT1/runt-related transcription factor 1 pathway. Inducible downregulation of miR-27a, in turn, negatively regulated vesicular stomatitis virus-triggered type I IFN production, thus promoting vesicular stomatitis virus replication in macrophages. Mechanistically, we found that miR-27a directly targeted sialic acid-binding Ig-like lectin (Siglec)1 and E3 ubiquitin ligase tripartite motif-containing protein 27 (TRIM27), both of which were previously verified as negative regulators of type I IFN production. Furthermore, we constructed "Sponge" transgenic mice against miR-27a expression and found that Siglec1 and TRIM27 expression were elevated whereas type I IFN production was inhibited and viral replication was aggregated in vivo. Therefore, type I IFN-induced downregulation of miR-27a can upregulate Siglec1 and TRIM27 expression, feedback inhibiting type I IFN production in antiviral innate response. Our study outlines a new negative way to feedback regulate type I IFN production.

PMID:
26700765
DOI:
10.4049/jimmunol.1502134
[Indexed for MEDLINE]
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