title: Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21.
abstract: 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 kinase1/2 and nuclear factor-κB 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 miR-21-regulated messenger RNAs revealed that 80% of the CSF-1-regulated canonical miR-21 targets are proinflammatory molecules. Additionally, miR-21 positively regulates M2 marker expression. Moreover, miR-21 feeds back to positively regulate its own expression and to limit CSF-1R-mediated activation of extracellular signal-regulated kinase1/2 and nuclear factor-κB. 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 monocyte/macrophage response to lipopolysaccharide. These results identify the CSF-1R-regulated miR-21 network that modulates macrophage polarization.
authors.affiliation: Department of Developmental and Molecular Biology, and.
authors.forename: Cristina I
authors.identifier: http://orcid.org/0000-0003-4200-2779
authors.initials: CI
authors.lastname: Caescu
authors.affiliation: The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY; Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN; and.
authors.forename: Xingyi
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Microbiology and Immunology, and.
authors.forename: Lydia
authors.initials: L
authors.lastname: Tesfa
authors.affiliation: Department of Developmental and Molecular Biology, and.
authors.forename: Tushar D
authors.initials: TD
authors.lastname: Bhagat
authors.affiliation: Department of Developmental and Molecular Biology, and.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY; Department of Genetics, and Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Developmental and Molecular Biology, and.
authors.forename: E Richard
authors.identifier: http://orcid.org/0000-0002-2910-2065
authors.initials: ER
authors.lastname: Stanley
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D053263:Gene Regulatory Networks; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D016186:Receptor, Macrophage Colony-Stimulating Factor