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

ABSTRACT: Macrophage polarization between the M2 (repair, pro-tumorigenic) and M1 (inflammatory) phenotypes is seen as a continuum of states. The detailed transcriptional events and signals downstream of CSF-1R that contribute 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 miR-21 as a downstream molecular switch controlling macrophage activation and identified ERK1/2 and NF-M-NM-:B as CSF-1R pTyr-721-regulated signaling nodes. We show that CSF-1R pTyr-721 signaling suppresses the proinflammatory phenotype, predominantly by induction of miR-21. Profiling of the miR-21-regulated mRNAs revealed that 80% of the CSF-1-regulated canonical miR-21 targets are pro-inflammatory 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 ERK1/2 and NF-M-NM-:B. 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 (LPS). M-bM-^@M-^C These results identify the macrophage miR-21 network as a novel target for controlling macrophage polarization. We performed microarray-based analysis on four mouse macrophage cell lines, two CSF-1R pTyr-721-expressing cell lines (M-/-.WT and M-/-.3ABY721) and two CSF-1R Tyr-721-deficient lines (M-/-.Y721F and M-/-.3AB). Total RNA (two biological replicates) was extracted from CSF-1-starved cells (UR) or from cells constitutively grown in CSF-1 (CONST). Additionally, CSF-1-starved M-/-.WT and M-/-.Y721F cell lines were stimulated with CSF-1 for 0min, 20 min, 60 min and 180 min and used for total RNA extraction. Total RNA preparations with Ribosomal Integrity Numbers (RIN) > 9.5 were used for microarray analysis. A total of 100 ug/cell line/replicate was used for gene expresion analysis on the Affymetrix Mouse Gene ST1.0 chips at the Genomics Core at Einstein, according to manufacturerM-bM-^@M-^Ys instructions. Differential expression analysis was performed using the M-bM-^@M-^XlimmaM-bM-^@M-^Y package of R/Bioconductor to identify significantly differentially expressed mRNAs over time, in response to CSF-1 treatment and to the genotype. CSF1-regulated genes were identified according to the cutoff with both expression folder change > 1.5 and p-value < 0.05.

SUBMITTER: E. Richard Stanley 

PROVIDER: E-GEOD-62630 | BioStudies | 2014-10-23


REPOSITORIES: biostudies

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