Abstract 9815: Loss of Inhibitory Fcgamma Receptor II is not Sufficient to Promote Atherosclerosis in Hyperlipidemic Apoe Knockout Mice

• Published in: Circulation (New York, N.Y.) Vol. 128; no. suppl_22
• Main Authors: Zhu, Xinmei, Ng, Hangpong, Nagarajan, Shanmugam
• Format: Journal Article
• Language: English
• Published: 26.11.2013
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.128.suppl_22.A9815

Abstract only 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, FcRIIb B6 ) mice. On the contrary to our hypothesis, compared to apoE KO mice apoE-FcRIIb double knockout mice (FcRIIb B6 ) 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, FcRIIb mixed ). Molecular mechanisms to understand the difference revealed that FcRIIb mixed mice showed more Th1 response (more IFN-gamma, TNF-alpha), while congenic FcRIIb B6 showed predominant Th2 responses (more IL-10, IL5, and IL-13). Moreover, anti-oxLDL IgG subtypes analyses showed elevated mIgG2a (Th1) response in FcRIIb mixed mice, while mIgG1 (Th2) levels were more predominant in FcRIIb B6 mice. Interestingly, circulating levels of autoantibodies, anti-nuclear antibodies, which have been implicated in autoimmune diseases such as lupus also was elevated in FcRIIb mixed compared to FcRIIb B6 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.