MiRNA regulation of macrophage inflammatory phenotype

Abstract

Abstract Classically (M1) and alternatively activated (M2) macrophages play distinct roles in various physiological and disease processes. M1 responses can cause inflammatory disease and tissue damage while M2 macrophages can limit inflammation and promote tissue repair. Therefore, understanding key players driving M1 or M2 phenotype may provide novel targets for therapeutic intervention. MicroRNA are small RNAs that bind to messenger RNA and post-transcriptionally modify gene expression and miR-155 has been associated with inflammatory phenotype. miR-155 was up-regulated more than 100-fold in M1, but not M2 macrophages, and inflammatory genes and proteins that define the M1 phenotype (e.g., iNOS, IL-1b, TNF-a) were reduced up to 72% in miR-155 knockout mouse macrophages. In contrast, miR-155 deficiency did not affect expression of genes associated with M2 macrophages (e.g., Arginase-1). Comparative transcriptional profiling of macrophages derived from wild-type and miR-155 knockout mice revealed that approximately half of the wild-type M1 signature was dependent on miR-155. Among miR-155-dependent M1 inflammatory effectors we found IL-6, iNOS, IL-1b, TNF-a and IL-12 as well as the recently described M1 marker CD38. miR-155 targets Bat5, Mafb, c-Maf, Bach1, Ptprj and Il6ra were increased in miR-155 KO M1 macrophages. Importantly, treatment with a miR-155 oligonucleotide inhibitor suppressed iNOS and TNF-a gene expressions in wild-type M1 macrophages, lending support to the idea that miR-155 targeting may be beneficial in inflammatory disease. Overall, these data indicate that miR-155 plays an essential role in the differentiation and effector potential of inflammatory M1 macrophages.