Reduced Atherosclerosis in apoE-inhibitory FcγRIIb–Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages. Issue 5 (May 2015)

• Record Type: Journal Article
• Authors: Ng, Hang Pong; Zhu, Xinmei; Harmon, Erin Y.; Lennartz, Michelle R.; Nagarajan, Shanmugam
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 35:Issue 5(2015)
• Publication Date: 2015-05
• Subjects: antibody production -- atherosclerosis -- autoimmune diseases -- Fc gamma receptors -- oxidized low-density lipoprotein; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.115.305290
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : 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 (monocyte chemoattractant protein-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. Abstract : Supplemental Digital Content is available in the text.