Hang Pong Ng1, Xinmei Zhu1, Erin Y Harmon1, Michelle R Lennartz1, Shanmugam Nagarajan2. 1. From the Department of Pathology, Vascular Medicine Institute, University of Pittsburgh, PA (H.P.N., X.Z., S.N.); Department of Microbiology and Immunology (H.P.N., S.N.), University of Arkansas for Medical Sciences, Little Rock; and Center for Cell Biology and Cancer Research, Albany Medical College, NY (E.Y.H., M.R.L.). 2. From the Department of Pathology, Vascular Medicine Institute, University of Pittsburgh, PA (H.P.N., X.Z., S.N.); Department of Microbiology and Immunology (H.P.N., S.N.), University of Arkansas for Medical Sciences, Little Rock; and Center for Cell Biology and Cancer Research, Albany Medical College, NY (E.Y.H., M.R.L.). Nagarajans@upmc.edu.
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.
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 miceattenuated 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.
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