MiR-3473b,miR-133b And MiR-5130Suppress Priming Of Macrophage Activation By Interferon γ And The Underlying Mechanisms

Macrophages are major effector cells of the innate immune system, and classical activation of macrophage function requires interferon y pretreatment (priming) and TLR stimuli. IFN-y-primed, LPS-activated macrophages produce elevated levels of proinflammatory cytokines while lower level of the anti-inflammatory cytokine IL-10. Also, the IFN-y-primed macrophages adapted a more activated morphology after LPS stimulation. In this study, we discovered that miR-3473b, miR-133b-5p and miR-5130were down-regulated after IFN-y priming, and overexpression of these miRNAs abrogated the priming function of IFN-y. Decreased expression of miR-133b-5p and miR-5130suppressed the phosphorylation of AKT and GSK3, leading to the diminished IL-10production. Overexpression of miR-3473b resulted in the augmented Akt phosphorylation. Moreover, miR-3473b targeted PTEN, and PTEN knowdown in macrophages mimicked the phenotype of BMM overexpressed with miR-3473b. In summary, our data demonstrate that IFN-y increases the activation of GSK3in macrophages by suppressing the expression of miR-3473b, miR-133b-5p and miR-5130. IFN-γ abrogates a potent TLR-induced inhibitory feedback loop by suppressing the production of the anti-inflammatory cytokine IL-10, leading to the increased inflammatory gene expression.