Reduced Atherosclerosis in apoE-inhibitory FcγRIIb–Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages
Objective—Fcγ receptors (FcγRs) are classified as activating (FcγRI, III, and IV) and inhibitory (FcγRII) receptors. We have reported that deletion of activating FcγRs in apolipoprotein E (apoE) single knockout mice attenuated atherosclerosis. In this report, we investigated the hypothesis that deficiency of inhibitory FcγRIIb exacerbates atherosclerosis.
Approach and Results—ApoE-FcγRIIb double knockout mice, congenic to the C57BL/6 (apoE-FcγRIIbB6−/−), were generated and atherosclerotic lesions were assessed. In contrary to our hypothesis, when compared with apoE single knockout mice, arterial lesions were significantly decreased in apoE-FcγRIIbB6−/− male and female mice fed chow or high-fat diets. Chimeric mice generated by transplanting apoE-FcγRIIbB6−/− marrow into apoE single knockout mice also developed reduced lesions. CD4+ T cells from apoE-FcγRIIbB6−/− mice produced higher levels of interleukin-10 and transforming growth factor-β than their apoE single knockout counterparts. As our findings conflict with a previous report using apoE-FcγRIIb129/B6−/− mice on a mixed genetic background, we investigated whether strain differences contributed to the anti-inflammatory response. Macrophages from FcγRIIb129/B6−/− mice on a mixed genetic background produced more interleukin-1β and MCP-1 in response to immune complexes, whereas congenic FcγRIIbB6−/− mice generated more interleukin-10 and significantly less interleukin-1β. Interestingly, the expression of lupus-associated slam genes, located in proximity to fcgr2b in mouse chromosome 1, is upregulated only in mixed FcγRIIb129/B6−/− mice.
Conclusions—Our findings demonstrate a detrimental role for FcγRIIb signaling in atherosclerosis and the contribution of anti-inflammatory cytokine responses in the attenuated lesions observed in apoE-FcγRIIbB6−/− mice. As 129/sv genome–derived lupus-associated genes have been implicated in lupus phenotype in FcγRIIb129/B6−/− mice, our findings suggest possible epistatic mechanism contributing to the decreased lesions.
- Received February 19, 2015.
- Accepted February 27, 2015.
- © 2015 American Heart Association, Inc.