Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

Macrophage polarization between the M2 (repair, protumorigenic) and M1 (inflammatory) phenotypes is seen as a continuum of states. The detailed transcriptional events and signals downstream of colony-stimulating factor 1 receptor (CSF-1R) that contributes to amplification of the M2 phenotype and suppression of the M1 phenotype are largely unknown. Macrophage CSF-1R pTyr-721 signaling promotes cell motility and enhancement of tumor cell invasion in vitro. Combining analysis of cellular systems for CSF-1R gain of function and loss of function with bioinformatic analysis of the macrophage CSF-1R pTyr-721 regulated transcriptome, we uncovered microRNA-21 (miR-21) as a downstream molecular switch controlling macrophage activation and identified extracellular signal-regulated kinase112 and nuclear factor-kappa B as CSF-1R pTyr-721 regulated signaling nodes. We show that CSF-1R pTyr-721 signaling suppresses the inflammatory phenotype, predominantly by induction of miR-21. Profiling of the miR21 regulated messenger RNAs revealed that 80% of the CSF-1 regulated canonical miR21 targets are proinflammatory molecules. Additionally, miR-21 positively regulates M2 marker expression. Moreover, mi R-21 feeds back to positively regulate its own expression and to limit CSF-1 R mediated activation of extracellular signal-regulated kinase112 and nuclear factor-KB. Consistent with an anti-inflammatory role of miRNA-21, intraperitoneal injection of mice with a miRNA-21 inhibitor increases the recruitment of inflammatory monocytes and enhances the peritoneal monocytelmacrophage response to lipopolysaccharide. These results identify the CSF-1R regulated mi R-21 network that modulates macrophage polarization.