Inhibition of Th17 cells and promotion of Tregs in Fcγ chain-deficient mice contributes to the attenuated atherosclerotic lesions (112.1)

Abstract

Abstract The presence of anti-oxLDL IgG is well documented in clinical and animal studies. However, the role for FcγRs to the progression of atherosclerosis has not been studied in detail. In the present study, we investigated the role for activating FcγR in the progression of atherosclerosis using apoE-Fcγ-chain double knockout (DKO) mice. Relative to apoE KO mice, arterial lesion formation was significantly decreased in apoE-Fcγ-chain DKO mice. Bone marrow chimera studies showed reduced lesions in apoE KO mice receiving the bone marrow of apoE-Fcγ-chain DKO mice. Cytokine responses by activated CD4+ cells showed higher levels of both IL-10 and IFN-γ secretion. Moreover, compared to apoE KO mice, anti-oxLDL IgG1 (Th2) and IgG2a (Th1) were increased in apoE-Fcγ-chain DKO mice. Interestingly, the number of Th17 cells and the secretion of IL-17 by activated CD4+ cells were decreased in apoE-Fcγ-chain DKO mice. Notably, the number of T-regulatory cells, expression of mRNA, and secretion of TGF-β and IL-10 were increased in apoE-Fc-chain DKO mice. Furthermore, secretions of IL-6 and STAT-3 phosphorylation essential for Th17 cell genesis were reduced in apoE-Fcγ-chain DKO mice. Collectively, our data suggest that activating FcγR promotes atherosclerosis by inducing Th17 response in the hyperlipidemic apoE KO mouse model. Our findings indicate that blocking activating FcγR may be a possible therapeutic approach to inhibit T cell responses contributing to the progression of atherosclerosis.