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

Signal-regulatory protein α (SIRPα) is an essential signaling molecule that modulates leukocyte inflammatory responses. However, the regulation of selective SIRPα synthesis and its dynamic changes in leukocytes under inflammatory stimulation remain incompletely understood.

We sought to identify the microRNAs (miRNAs) that posttranscriptionally regulate SIRPα synthesis and their roles in modulating macrophage inflammatory responses.

SIRPα was induced in SIRPα-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 SIRPα synthesis in leukocytes and leukocyte inflammatory responses were determined.

We identified SIRPα as a common target gene of miR-17, miR-20a, and miR-106a. During SIRPα 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 SIRPα 3' untranslated region and correlated inversely with SIRPα 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 SIRPα 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 SIRPα.

These findings demonstrate for the first time that miR-17, miR-20a, and miR-106a regulate SIRPα synthesis and SIRPα-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.