title: Hematopoietic miR155 deficiency enhances atherosclerosis and decreases plaque stability in hyperlipidemic mice.
abstract: microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory mediators. Although miR155 is considered to be a pro-inflammatory microRNA, in vitro reports show anti-inflammatory effects in lipid-loaded cells. In this study we examined the role of miR155 in atherosclerosis in vivo using bone marrow transplantation from miR155 deficient or wildtype mice to hyperlipidemic mice. Hematopoietic deficiency of miR155 enhanced atherosclerotic plaque development and decreased plaque stability, as evidenced by increased myeloid inflammatory cell recruitment to the plaque. The increased inflammatory state was mirrored by a decrease in circulating CD4(+)CD25(+)FoxP3(+) regulatory T cells, and an increase in granulocytes (CD11b(+)Ly6G(+)) in blood of miR155(-/-) transplanted mice. Moreover, we show for the first time a crucial role of miR155 in monocyte subset differentiation, since hematopoietic deficiency of miR155 increases the 'inflammatory' monocyte subset (CD11b(+)Ly6G(-)Ly6C(hi)) and reduces 'resident' monocytes (CD11b(+)Ly6G(-)Ly6C(low)) in the circulation. Furthermore, cytokine production by resident peritoneal macrophages of miR155(-/-) transplanted hyperlipidemic mice was skewed towards a more pro-inflammatory state since anti-inflammatory IL-10 production was reduced. In conclusion, in this hyperlipidemic mouse model miR155 acts as an anti-inflammatory, atheroprotective microRNA. Additionally, besides a known role in lymphoid cell development, we show a crucial role of miR155 in myeloid lineage differentiation.
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. Marjo.donners@maastrichtuniversity.nl
authors.forename: Marjo M P C
authors.initials: MM
authors.lastname: Donners
authors.forename: Ine M J
authors.initials: IM
authors.lastname: Wolfs
authors.forename: Lauran J
authors.initials: LJ
authors.lastname: Stöger
authors.forename: Emiel P C
authors.initials: EP
authors.lastname: van der Vorst
authors.forename: Chantal C H
authors.initials: CC
authors.lastname: Pöttgens
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.forename: Marion J J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Menno P J
authors.initials: MP
authors.lastname: de Winther
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D019070:Cell Lineage / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006098:Granulocytes / Q000276:immunology; D006949:Hyperlipidemias / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D017384:Sequence Deletion; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058408:Th1-Th2 Balance
chemical_list: D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse