title: Regulation of Csf1r and Bcl6 in macrophages mediates the stage-specific effects of microRNA-155 on atherosclerosis.
abstract: OBJECTIVE
  The function of microRNAs is highly context and cell type dependent because of their highly dynamic expression pattern and the regulation of multiple mRNA targets. MicroRNA-155 (miR-155) plays an important role in the innate immune response by regulating macrophage function; however, the effects of miR-155 in macrophages on atherosclerosis are controversial. We hypothesized that the stage-dependent target selection of miR-155 in macrophages determines its effects on atherosclerosis.
  
  
  RESULTS
  The expression of miR-155 increased in lesional macrophages of apolipoprotein E-deficient mice between 12 and 24 weeks of a high-cholesterol diet. Mir155 knockout in apolipoprotein E-deficient mice enhanced lesion formation, increased the lesional macrophage content, and promoted macrophage proliferation after 12 weeks of the high-cholesterol diet. In vitro, miR-155 inhibited macrophage proliferation by suppressing colony-stimulating factor-1 receptor, which was upregulated in lesional macrophages of Mir155(-/-) apolipoprotein E-deficient mice. By contrast, Mir155 deficiency reduced necrotic core formation and the deposition of apoptotic cell debris, thereby preventing the progression of atherosclerosis between 12 and 24 weeks of the high-cholesterol diet. miR-155 inhibited efferocytosis in vitro by targeting B-cell leukemia/lymphoma 6 and thus activating RhoA (ras homolog gene family, member A). Accordingly, B-cell leukemia/lymphoma 6 was upregulated in lesional macrophages of Mir155(-/-) apolipoprotein E-deficient mice after 24 weeks, but not after 12 weeks of the high-cholesterol diet.
  
  
  CONCLUSIONS
  Our findings demonstrate a stage-specific role of miR-155 in lesion formation. miR-155 suppressed macrophage proliferation by targeting colony-stimulating factor-1 receptor in early and impaired efferocytosis by downregulating B-cell leukemia/lymphoma 6 in advanced atherosclerosis. Therefore, targeting the interaction between miR-155 and B-cell leukemia/lymphoma 6 may be a promising approach to inhibit the progression of atherosclerosis.
authors: From the Experimental Vascular Medicine, Institute for Cardiovascular Prevention, Medical Faculty of Ludwig-Maximilians-University Munich, Munich, Germany (Y.W., M.Z., J.C.-C., K.H., C.W., A.S.); Institute for Molecular Cardiovascular Research, Medical Faculty of RWTH Aachen University, Aachen, Germany (Y.W., J.C.-C., K.H., C.W., A.S.); and Munich Heart Alliance, Munich, Germany (C.W., A.S.).
authors: Yuanyuan
authors: Y
authors: Wei
authors: From the Experimental Vascular Medicine, Institute for Cardiovascular Prevention, Medical Faculty of Ludwig-Maximilians-University Munich, Munich, Germany (Y.W., M.Z., J.C.-C., K.H., C.W., A.S.); Institute for Molecular Cardiovascular Research, Medical Faculty of RWTH Aachen University, Aachen, Germany (Y.W., J.C.-C., K.H., C.W., A.S.); and Munich Heart Alliance, Munich, Germany (C.W., A.S.).
authors: Mengyu
authors: M
authors: Zhu
authors: From the Experimental Vascular Medicine, Institute for Cardiovascular Prevention, Medical Faculty of Ludwig-Maximilians-University Munich, Munich, Germany (Y.W., M.Z., J.C.-C., K.H., C.W., A.S.); Institute for Molecular Cardiovascular Research, Medical Faculty of RWTH Aachen University, Aachen, Germany (Y.W., J.C.-C., K.H., C.W., A.S.); and Munich Heart Alliance, Munich, Germany (C.W., A.S.).
authors: Judit
authors: J
authors: Corbalán-Campos
authors: From the Experimental Vascular Medicine, Institute for Cardiovascular Prevention, Medical Faculty of Ludwig-Maximilians-University Munich, Munich, Germany (Y.W., M.Z., J.C.-C., K.H., C.W., A.S.); Institute for Molecular Cardiovascular Research, Medical Faculty of RWTH Aachen University, Aachen, Germany (Y.W., J.C.-C., K.H., C.W., A.S.); and Munich Heart Alliance, Munich, Germany (C.W., A.S.).
authors: Kathrin
authors: K
authors: Heyll
authors: From the Experimental Vascular Medicine, Institute for Cardiovascular Prevention, Medical Faculty of Ludwig-Maximilians-University Munich, Munich, Germany (Y.W., M.Z., J.C.-C., K.H., C.W., A.S.); Institute for Molecular Cardiovascular Research, Medical Faculty of RWTH Aachen University, Aachen, Germany (Y.W., J.C.-C., K.H., C.W., A.S.); and Munich Heart Alliance, Munich, Germany (C.W., A.S.).
authors: Christian
authors: C
authors: Weber
authors: From the Experimental Vascular Medicine, Institute for Cardiovascular Prevention, Medical Faculty of Ludwig-Maximilians-University Munich, Munich, Germany (Y.W., M.Z., J.C.-C., K.H., C.W., A.S.); Institute for Molecular Cardiovascular Research, Medical Faculty of RWTH Aachen University, Aachen, Germany (Y.W., J.C.-C., K.H., C.W., A.S.); and Munich Heart Alliance, Munich, Germany (C.W., A.S.). aschober@med.lmu.de.
authors: Andreas
authors: A
authors: Schober
mesh_terms: D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D051560:Proto-Oncogene Proteins c-bcl-6; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D001057:Apolipoproteins E; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D051560:Proto-Oncogene Proteins c-bcl-6; D002784:Cholesterol; D016186:Receptor, Macrophage Colony-Stimulating Factor; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: atherosclerosis; macrophages; microRNAs