Abstract 13667: Suppressor of Cytokine Signaling-1 Controls Early Murine Atherosclerosis by Regulating Pro-Atherogenic Ly-6Chi Monocyte and Macrophage Formation
Background: In early atherogenesis, lesion development is characterized by the migration of circulating Ly-6Chi monocytes into the arterial wall, differentiation into macrophages, and foam cell formation upon oxidized lipoprotein ingestion. Suppressor of cytokine signaling (socs)-1 has been demonstrated to regulate major inflammatory pathways and shape macrophage and monocyte phenotype. We here investigated the impact of socs-1 on Ly-6Chi monocytes and macrophages in murine atherosclerosis.
Methods and Results: As socs-1-/- mice die due to uncontrolled interferon-gamma (IFNg) signaling, recombination activating gene (rag)-2-/-;socs-1-/- mice lacking mature lymphocytes, the major source for IFNg were crossed with atherosclerosis-prone low-density lipoprotein receptor (ldlr-/-) animals. Atherosclerosis was investigated after 4 weeks of high-cholesterol dieting (HCD) starting directly after weaning. Oil-Red-O staining of aortas demonstrated increased lesion formation in socs-1-/-triple-KO mice (N=8-15mice/group, p<0.05 vs ldlr-/- and ldlr-/-;rag-2-/-mice). While cell sorting experiments revealed enhanced circulating CD11b+,Ly-6Chi monocytes in socs-1-/- triple-KO-mice under chow diet(CD), circulating monocytes decreased in socs-1-/-triple KO-mice after 4 weeks of HCD compared to mice under CD while bone-marrow and splenic CD11b+,Ly-6Chi monocyte content remained enhanced (N=9-15mice/group, p<0.05). However, immunohistochemical analysis indicated an increase of Ly-6C positive cells in atherosclerotic plaques of socs-1-/-triple-KO mice compared to ldlr-/- and ldlr-/-;rag-2-/-mice. Ex-vivo experiments demonstrated that scavenger receptor CD36 expression and foam cell formation were significantly enhanced in bone-marrow derived macrophages (BMDM) from socs-1-/-triple-KO mice (N=5-13mice/group, p<0.05 vs ldlr-/- and ldlr-/-;rag-2-/- mice). Subsequently, we observed increased macrophage accumulation and lipid depositions in aortic roots of socs-1-/- triple-KO mice.
Summary and Conclusion: Socs-1 controls early atherogenesis by regulating pro-inflammatory CD11b+,Ly-6Chi monocyte formation, migration and accumulation of macrophages in developing atherosclerotic lesions.
- © 2011 by American Heart Association, Inc.