MiR-145 Promotes Interleukin 10 Production In TLR/RIG-I-triggered Macrophages Via Targeting Histone Deacetylase HDAC11

Anti-inflammatory cytokine interleukin-10 (IL-10) plays critical roles in the regulation of immune response, and the detailed mechanism that regulates IL-10 production has attracted much attention. Although multiple regulators, including signaling molecules, transcription factors, and epigenetic regulators, have been extensively investigated in the regulation of IL-10 production, there are limited reports about the regulation of IL-10 production and its functions by microRNAs (miRNAs). miRNAs, the new-found small non-coding RNAs, have been demonstrated to be important regulators in various biological process, including immune response. However, the miRs which are regulated by innate signals and invovled in the subsequent innate response need to be further determined. In the present study, through miRNA microarray, we found that miR-145/miR-143 cluster was significantly down-regulated upon TLR and RIG-I signal activation in mouse peritoneal macrophages. In order to investigate its biological significance and the underlying mechanism in TLR-or RIG-I-activated innate immune response, we showed that TLR and RIG-I activation-mediated miR-145/miR-143 down-regulation was dependent on type I Interferon production and its downstream signaling. Furthermore, functional studies demonstrated that miR-145 could enhance IL-10 production in LPS-treated macrophages, which in turn suppressed inflammatory IL-12p70 production. As miRNAs function mainly through posttranscriptional inhibition of their target genes, miR-145 was suggested to exert its immune modulatory function through directly targeting histone deacetylase HDAC11 expression, which is an epigenetic Il10 gene silencer. Together, our results demonstrated that miR-145, down-regulated upon type I interferon signal, could promote IL-10 production via posttranscriptional inhibition of epigenetic regulator HDAC11 expression.