Anti‐Inflammatory Immune Skewing Is Atheroprotective: Apoe −/− Fcγ RII b −/− Mice Develop Fibrous Carotid Plaques

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 Fcγ RII b in carotid plaque development and stability in apolipoprotein (Apo)e −/− and Apoe −/− Fcγ RII b −/− double knockout ( DKO ) animals. Methods and 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 (T regs ) 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 Fcγ RII b would exacerbate atherosclerosis and generate unstable plaques. However, we found that deletion of Fcγ RII b on a congenic C57 BL /6 background induces an anti‐inflammatory T reg /M2 polarization that is atheroprotective.