title: Enhancement of macrophage inflammatory responses by CCL2 is correlated with increased miR-9 expression and downregulation of the ERK1/2 phosphatase Dusp6.
abstract: Macrophage polarization plays a central role in both protective immunity and immunopathology. While the role of cytokines in driving macrophage polarization is well characterized, less is understood about the role of chemokines. The purpose of this study was to determine if CC chemokine 2 (CCL2/MCP1) could influence macrophage polarization in response to subsequent activation with cytokines and microbial products. Treatment of bone marrow-derived macrophages with CCL2 alone did not result in increased expression of either classical or alternatively-activated macrophage genes as compared to standard skewing cytokines or Toll-like receptor agonists. However, subsequent stimulation of CCL2 pre-treated macrophages with classical activation stimuli resulted in enhanced expression of genes associated with classical activation. This enhancement correlated with increased phosphorylation of ERK1/2 kinases, a decrease in expression of the ERK phosphatase Dusp6 and enhanced expression of miR-9. These results indicate that CCL2 supports the classical activation of macrophages, with miR-9 mediated down-regulation of Dusp6 and enhanced ERK-mediated signal transduction possibly mediating this enhanced pro-inflammatory gene expression.
authors.affiliation: Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. Electronic address: wfcarson@umich.edu.
authors.forename: William F
authors.initials: WF
authors.lastname: Carson
authors.affiliation: Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. Electronic address: sarahesgreen@gmail.com.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Salter-Green
authors.affiliation: Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. Electronic address: scolam@umich.edu.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Scola
authors.affiliation: Department of Vascular Surgery, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: ajoshi@umich.edu.
authors.forename: Amrita
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Department of Vascular Surgery, University of Michigan Medical School, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. Electronic address: kgallag@umich.edu.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Gallagher
authors.affiliation: Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA. Electronic address: slkunkel@umich.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000276:immunology*; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; C551804:MIRN9 microRNA, mouse; D035683:MicroRNAs; D051193:Toll-Like Receptors; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse
keywords: Chemokines; Gene regulation; Macrophages; Micro-RNA; Signal transduction