MicroRNAs of the miR-17~92 family inhibit macrophage activation and inflammation

Abstract

Abstract Production of pro- and anti-inflammatory cytokines by macrophages is tightly controlled by multiple layers of mechanisms including those involving miRNA-mediated regulation of post-transcriptional events. By genetically deleting all three individual miRNA clusters in the miR-17~92 family, we found that this family of miRNAs inhibit macrophage activation by promoting expression of a key anti-inflammatory cytokine IL-10 and thus suppress production of pro-inflammatory mediators such as TNF. Consistent with the heightened inflammatory responses in vitro, myeloid-specific ablation of miR-17~92 family miRNAs in vivo led to exacerbated obesity under the condition of a high-fat diet and poor survival in the DSS-induced colitis model. Moreover, miRNA-deficient adipose tissue macrophages and intestinal macrophages exhibited enhanced levels of TNF and reduced levels of IL-10. Mechanistically, miR-17~92 family miRNAs sustained IL-10 production in macrophages by promoting transcription of the Fos gene encoding a key transcription factor driving Il10 expression. The positive effects of miR-17~92 family miRNAs on Fos expression are secondary to negative regulation of Fos by transcription factor YY1 that is a direct target of miR-17~92 family miRNAs. Taken together, these results identified miR-17~92 family miRNAs as crucial regulators of the balance between pro- and anti-inflammatory cytokines and illustrated key roles for three clusters of the miR-17~92 family in cooperatively regulating macrophage activation and inflammatory responses.