Abstract 9815: Loss of Inhibitory Fcgamma Receptor II is not Sufficient to Promote Atherosclerosis in Hyperlipidemic Apoe Knockout Mice
Hypothesis: Elevated anti-oxidized LDL IgG and its interaction with Fcgamma receptors (FcR) have been suggested to be associated with the progression of atherosclerosis. Four different classes of FcRs, FcRI, FcRII, FcRIII, and FcRIV, have been characterized in mice. Functionally, FcRs can be classified into the activating (FcRI, III, and IV) and inhibitory (FcRII) receptors. Previous finding from our lab and others have shown that deletion of activating Fcgamma receptors (I, III and IV) in apoE KO mice decreased atherosclerosis. This led to our hypothesis that deficiency of inhibitory FcRII exacerbates atherosclerosis.
Methods and Results: We tested this hypothesis using apoE-FcRIIb double knockout (congenic to C57BL/6, FcRIIbB6) mice. On the contrary to our hypothesis, compared to apoE KO mice apoE-FcRIIb double knockout mice (FcRIIbB6) fed chow or high-fat diets did not show exacerbated atherosclerotic lesions (n=10/group). Our finding is in contrast to previous reports showing exacerbated lesions in apoE-FcRIIb mice in a mixed background (129s/v and C57BL/6, FcRIIbmixed). Molecular mechanisms to understand the difference revealed that FcRIIbmixed mice showed more Th1 response (more IFN-gamma, TNF-alpha), while congenic FcRIIbB6 showed predominant Th2 responses (more IL-10, IL5, and IL-13). Moreover, anti-oxLDL IgG subtypes analyses showed elevated mIgG2a (Th1) response in FcRIIbmixed mice, while mIgG1 (Th2) levels were more predominant in FcRIIbB6 mice. Interestingly, circulating levels of autoantibodies, anti-nuclear antibodies, which have been implicated in autoimmune diseases such as lupus also was elevated in FcRIIbmixed compared to FcRIIbB6 mice.
Conclusion: These findings revealed a novel paradigm that inhibitory FcRIIb does not directly contribute to atherosclerosis. However, in the presence of lupus susceptible gene loci, inhibitory FcRIIb exacerbates the progression of atherosclerosis. As FcRIIb polymorphism has been implicated in lupus susceptibility, the role of FcRIIb, as pro-atherosclerotic mediators in vivo in lupus-associated cardiovascular disease need to be investigated.
- © 2013 by American Heart Association, Inc.