Abstract 19754: Specific Overexpression of Fc Gamma Receptor IIb on Macrophages Reduces Atherosclerosis in Ldlr Deficient Mice
Fc receptors for Ig are key players in regulating innate and adaptive immunity. Activation of Fc receptor triggers phagocytosis, inflammatory cytokine-release, antigen presentation, and regulation of humoral responses. FcγRIIb plays a unique role in negatively regulating immune responses. Atherosclerosis is an inflammatory disease in which monocytes/macrophages play a prominent role. The generation of mice overexpressing FcγRIIb on macrophages (M-TG) allowed the exploration of the specific role of macrophage FcγRIIb expression in the development of atherosclerosis. We reconstituted lethally irradiated LDLr-deficient mice with bone marrow cells from either control or M-TG (LDLr−/−/M-TG) mice. After 4weeks of recovery, mice were put on high fat diet during 10 weeks to induce atherosclerosis. We found that LDLr−/−/M-TG mice had 21% reduction of atherosclerotic lesion size at the aortic sinus compared with controls (542,128 ± 34,294 micro m2 for LDLr−/−/MTG vs 690,779 ± 31,939 micro m2 for LDLr−/−, P=0.01) despite similar plasma cholesterol levels in both groups. Circulating antibodies levels against MDA-LDL and Cuox-LDL were markedly decreased for IgG (−71% P<0.01) but not for IgM type in LDLr−/−/M-TG mice compared with controls. IgG reduction occurred mainly through a reduction of Th1 related isotype IgG2c. Flow cytometry analysis showed lower expression of CD69+ and CD44bright (−26% for both P=0.01) CD4+ T cells and lower percentage of IFNγ producing-CD4+ cells (−26% P=0.06) in the spleen of LDLr−/−/M-TG mice compared with controls. In conclusion, FcγRIIb overexpression on macrophages controls Th1 type immune responses in atherosclerosis and reduces lesion development.
- © 2010 by American Heart Association, Inc.