Objective:
Functionally, Fcgamma receptors (FcgRs) can be classified as activating (FcgRI, III, and IV) and inhibitory (FcgRII) receptors. We have reported that combined deficiency of all three activating FcgRs in apoE knockout mice decreased atherosclerosis. In this report, we investigated the independent role of FcgRI and FcgRIV in the progression of atherosclerosis. We investigated the hypothesis that the deficiency of FcgRIV, one of the activating FcgRs, inhibits atherosclerosis in a hypercholesterolemic mouse model. We tested the hypothesis that FcgRI and FcgRIV exacerbate atherosclerosis using apoE-FcgRI dKO and apoE-FcgRIV deficient mice.
Approach and Results:
ApoE-FcgRI and apoE-FcgRIV double knockout mice (dKO) congenic to the C57BL/6 were generated and atherosclerotic lesions were assessed. Our results show that arterial lesions were not different between apoE-FcgRI dKO and apoE knockout (apoE KO) mice. Interestingly, arterial lesions were significantly decreased in a regular chow or a high-fat diet fed apoE-FcgRIV dKO male and female mice, relative to apoE KO mice. Bone marrow chimeras were used to address the relative contribution of FcgRIV expressed on hematopoietic cells including macrophages and dendritic cell. ApoE KO mice transplanted with apoE-FcgRIV dKO marrow showed significantly reduced arterial lesions relative to recipient mice transplanted with apoE KO marrow. Next, we investigated whether pro-inflammatory response contributed to the pro-atherogenic effect of FcgRIV. Activated CD4+ T cells of apoE-FcgRIV dKO mice showed increased secretion of IL-10, whereas IFN-gamma and IL-17 by T cells were decreased. Interestingly, dendritic cells at the lesion-prone vascular site from apoE-FcgRIV dKO mice induced increased IL-10 secretion by LDL-specific T cells. Moreover, FcgRIV KO and apoE-FcgRIV dKO macrophages showed decreased inflammasome activation as evidenced by decreased IL-1 beta response.
Conclusions:
Our findings demonstrate that the pro-inflammatory responses initiated by FcgRIV, one of the activating FcgRs, contribute to the progression of atherosclerosis.
Understanding the progression of atherosclerosis through gene profiling and co-expression network analysis in Apob tm2Sgy Ldlr tm1Her double knockout mice
