MicroRNA-17/20a/106a modulate macrophage inflammatory responses through targeting signal-regulatory protein ?.

ABSTRACT: BACKGROUND:Signal-regulatory protein ? (SIRP?) is an essential signaling molecule that modulates leukocyte inflammatory responses. However, the regulation of selective SIRP? synthesis and its dynamic changes in leukocytes under inflammatory stimulation remain incompletely understood. OBJECTIVE:We sought to identify the microRNAs (miRNAs) that posttranscriptionally regulate SIRP? synthesis and their roles in modulating macrophage inflammatory responses. METHODS:SIRP? was induced in SIRP?-negative promyelocytic cells by retinoic acid or phorbol 12-myristate 13-acetate, and the differential expression of miRNAs was assessed by means of microarray and quantitative RT-PCR assays. The roles of identified miRNAs in controlling SIRP? synthesis in leukocytes and leukocyte inflammatory responses were determined. RESULTS:We identified SIRP? as a common target gene of miR-17, miR-20a, and miR-106a. During SIRP? induction, levels of these 3 miRNAs were all reduced, and their downregulation by retinoic acid or phorbol 12-myristate 13-acetate occurred through suppression of the c-Myc signaling pathway. All miR-17, miR-20a, and miR-106a specifically bound to the same seed sequence within the SIRP? 3' untranslated region and correlated inversely with SIRP? protein levels in various cells. In macrophages upregulation of miR-17, miR-20a, and miR-106a by LPS served as the mechanism underlying LPS-induced SIRP? reduction and macrophage activation. Both in vitro and in vivo assays demonstrate that miR-17, miR-20a, and miR-106a regulate macrophage infiltration, phagocytosis, and proinflammatory cytokine secretion through targeting SIRP?. CONCLUSION:These findings demonstrate for the first time that miR-17, miR-20a, and miR-106a regulate SIRP? synthesis and SIRP?-mediated macrophage inflammatory responses in a redundant fashion, providing a novel pathway in which a panel of miRNAs can modulate immune polarization through regulation of macrophage activation.

SUBMITTER: Zhu D 

PROVIDER: S-EPMC5882493 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature