title: Anti-inflammatory immune skewing is atheroprotective: Apoe−/−FcγRIIb−/− mice develop fibrous carotid plaques.
abstract: BACKGROUND
  Stroke, caused by carotid plaque rupture, is a major cause of death in the United States. Whereas vulnerable human plaques have higher Fc receptor (FcγR) expression than their stable counterparts, how FcγR expression impacts plaque histology is unknown. We investigated the role of FcγRIIb in carotid plaque development and stability in apolipoprotein (Apo)e−/− and Apoe−/−FcγRIIb−/− double knockout (DKO) animals.
  
  
  RESULTS
  Plaques were induced by implantation of a shear stress‐modifying cast around the carotid artery. Plaque length and stenosis were followed longitudinally using ultrasound biomicroscopy. Immune status was determined by flow cytometry, cytokine release, immunoglobulin G concentration and analysis of macrophage polarization both in plaques and in vitro. Surprisingly, DKO animals had lower plaque burden in both carotid artery and descending aorta. Plaques from Apoe−/− mice were foam‐cell rich and resembled vulnerable human specimens, whereas those from DKO mice were fibrous and histologically stable. Plaques from DKO animals expressed higher arginase 1 (Arg‐1) and lower inducible nitric oxide synthase (iNOS), indicating the presence of M2 macrophages. Analysis of blood and cervical lymph nodes revealed higher interleukin (IL)‐10, immune complexes, and regulatory T cells (Tregs) and lower IL‐12, IL‐1β, and tumor necrosis factor alpha (TNF‐α) in DKO mice. Similarly, in vitro stimulation produced higher IL‐10 and Arg‐1 and lower iNOS, IL‐1β, and TNF‐α in DKO versus Apoe−/− macrophages. These results define a systemic anti‐inflammatory phenotype.
  
  
  CONCLUSIONS
  We hypothesized that removal of FcγRIIb would exacerbate atherosclerosis and generate unstable plaques. However, we found that deletion of FcγRIIb on a congenic C57BL/6 background induces an anti‐inflammatory Treg/M2 polarization that is atheroprotective.
authors.affiliation: Centers for Cell Biology and Cancer Research, Albany Medical College, Albany, NY
authors.forename: Erin Y
authors.initials: EY
authors.lastname: Harmon
authors.forename: Van
authors.initials: V
authors.lastname: Fronhofer
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Keller
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Feustel
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhu
authors.forename: Hao
authors.initials: H
authors.lastname: Xu
authors.forename: Dorina
authors.initials: D
authors.lastname: Avram
authors.forename: David M
authors.initials: DM
authors.lastname: Jones
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Nagarajan
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Lennartz
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001119:Arginase / Q000378:metabolism; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism*; D016893:Carotid Stenosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D005838:Genotype; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D033401:Microscopy, Acoustic; D009336:Necrosis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D017452:Receptors, IgG / Q000172:deficiency* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; C499172:Fcgr2b protein, mouse; D018836:Inflammation Mediators; D017452:Receptors, IgG; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase