1. Hematopoietic miR155 Deficiency Enhances Atherosclerosis and Decreases Plaque Stability in Hyperlipidemic Mice
- Author
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Marion J.J. Gijbels, Emiel P. C. van der Vorst, Chantal C. H. Pöttgens, Stephane Heymans, Blanche Schroen, Lauran J. Stöger, Marjo M. P. C. Donners, Ine M. J. Wolfs, Menno P.J. de Winther, Other departments, Medical Biochemistry, ACS - Amsterdam Cardiovascular Sciences, AII - Amsterdam institute for Infection and Immunity, Moleculaire Genetica, Promovendi CD, Cardiologie, Pathologie, Genetica & Celbiologie, and RS: CARIM School for Cardiovascular Diseases
- Subjects
Male ,Myeloid ,Mouse ,medicine.medical_treatment ,lcsh:Medicine ,Cardiovascular ,T-Lymphocytes, Regulatory ,Monocytes ,Mice ,Molecular cell biology ,RNA interference ,Cell Movement ,Bone Marrow and Stem Cell Transplantation ,IL-2 receptor ,lcsh:Science ,Th1-Th2 Balance ,Bone Marrow Transplantation ,Sequence Deletion ,Multidisciplinary ,FOXP3 ,Animal Models ,Hematology ,Plaque, Atherosclerotic ,Haematopoiesis ,Cytokine ,medicine.anatomical_structure ,Cytokines ,Medicine ,Female ,medicine.symptom ,Research Article ,Immune Cells ,Immunology ,Hyperlipidemias ,Mice, Transgenic ,Inflammation ,Biology ,miR-155 ,Model Organisms ,Vascular Biology ,medicine ,Animals ,Cell Lineage ,Monocyte ,lcsh:R ,Atherosclerosis ,Hematopoiesis ,Disease Models, Animal ,MicroRNAs ,Immune System ,Macrophages, Peritoneal ,lcsh:Q ,Gene expression ,Granulocytes - 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.
- Published
- 2012
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