title: Reduced Atherosclerosis in apoE-inhibitory FcγRIIb-Deficient Mice Is Associated With Increased Anti-Inflammatory Responses by T Cells and Macrophages.
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.
  
  
  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.
authors: 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.).
authors: Hang Pong
authors: HP
authors: Ng
authors: 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.).
authors: Xinmei
authors: X
authors: Zhu
authors: 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.).
authors: Erin Y
authors: EY
authors: Harmon
authors: 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.).
authors: Michelle R
authors: MR
authors: Lennartz
authors: 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.
authors: Shanmugam
authors: S
authors: Nagarajan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D015704:CD4 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D017452:Receptors, IgG
keywords: Fc gamma receptors; antibody production; atherosclerosis; autoimmune diseases; oxidized low-density lipoprotein