MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

Abstract

Japanese encephalitis virus (JEV) can target CNS and cause neuroinflammation that is characterized by profound neuronal damage and concomitant microgliosis/astrogliosis. Although microRNAs (miRNAs) have emerged as a major regulatory network with profound effects on inflammatory response, it is less clear how they regulate JEV-induced inflammation. In this study, we found that miR-15b is involved in modulating the JEV-induced inflammatory response. The data demonstrate that miR-15b is upregulated during JEV infection of glial cells and mouse brains. In vitro overexpression of miR-15b enhances the JEV-induced inflammatory response, whereas inhibition of miR-15b decreases it. Mechanistically, ring finger protein 125 (RNF125), a negative regulator of RIG-I signaling, is identified as a direct target of miR-15b in the context of JEV infection. Furthermore, inhibition of RNF125 by miR-15b results in an elevation in RIG-I levels, which, in turn, leads to a higher production of proinflammatory cytokines and type I IFN. In vivo knockdown of virus-induced miR-15b by antagomir-15b restores the expression of RNF125, reduces the production of inflammatory cytokines, attenuates glial activation and neuronal damage, decreases viral burden in the brain, and improves survival in the mouse model. Taken together, our results indicate that miR-15b modulates the inflammatory response during JEV infection by negative regulation of RNF125 expression. Therefore, miR-15b targeting may constitute an interesting and promising approach to control viral-induced neuroinflammation.

Interplay between Inflammation and Cellular Stress Triggered by Flaviviridae Viruses

“…Activation of RIG-I-MAVS/STING pathways during JEV infection in neurons was associated to increased production of interferon, proinflammatory cytokines and reduction of intracellular levels of virus (Nazmi et al, 2011, 2012). On the other hand, it was demonstrated that JEV infection induced the expression of microRNAs, such as miRNA15b, which negatively regulates RIG-I signaling, contributing to virus escape from innate immune response (Zhu et al, 2015). …”

Human MicroRNA miR-532-5p Exhibits Antiviral Activity against West Nile Virus via Suppression of Host Genes SESTD1 and TAB3 Required for Virus Replication

“…In addition, roles of a number of mammalian miRNAs in response to Japanese encephalitis virus (JEV) infection have also been reported. miR-15b and miR-155 were shown to induce an inflammatory response in JEV-infected microglial cells via suppression of RNF125 (28) and SHIP1 (29), respectively, whereas miR-146a was shown to inhibit the immune response against JEV by suppressing the JAK/STAT pathway in mouse monocytes (30). WNV infection has been shown to alter the expression of the inflammatory miRNAs miR-196a, miR-202-3p, miR-449c, and miR125a-3p in the mouse brain (31).…”

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

“…Several miRNAs target transcripts encoding components at many steps of the type I IFN response, which introduced an additional layer of regulation for antiviral pathway, and these targeting transcripts include components of PRR pathways impacting IFN production, the IFN cell surface receptors, signal transduction proteins to regulate IFN signaling, and some IRGs (22). In the activation of the RIG-I antiviral pathway, a set of miRNA expressions are induced and they employ feedback regulatory mechanisms to modulate type I IFN production and function (23,24). Vesicular stomatitis virus (VSV) infection induces microRNA (miR)-146a expression, which subsequently suppresses type I IFN production by targeting IL-1R-associated kinases 1 and 2 and TNFR-associated factor 6 (25).…”