FcγRIIB on CD11c+ cells alters liver and adipose tissue inflammation affecting glucose tolerance and atherosclerosis in female mice

Abstract

Circulating levels of oxidized lipoprotein (oxLDL) correlate with myocardial infarction (MI) risk. Previous work demonstrates that oxLDL immune complexes can signal through FcγRs on bone marrow-derived dendritic cells (BMDCs), enhancing their activation and inflammatory cytokine secretion. While global FcγR−/− studies show that activating FcγRs are proatherogenic, the role of inhibitory FcγRIIb is unclear. We sought to determine the role of DC-specific FcγRIIb on atherosclerosis and glucose tolerance, as both are important MI risk factors. Bone marrow chimeras were generated by rescuing lethally irradiated female Ldlr−/− mice with hematopoietic cells from littermate CD11c-Cre+or CD11c-Cre− Fcgr2bfl/fl donors. Four weeks after transplant, recipients were placed on a Western diet for eight weeks. Quantitation of atherosclerosis in the proximal aorta demonstrated a 58% increase CD11c− Cre+ Fcgr2bfl/fl recipients. We discovered that hepatic cholesterol, scavenger receptor CD36, and MHC Class II were increased on CD11c+CD11b+ cells in CD11c-Cre+ Fcgr2bfl/fl recipients. Furthermore, study of aortic draining lymph nodes revealed a 50% reduction in TREGS. To study glucose tolerance, six-week-old CD11c-Cre+ and CD11c-Cre− Fcgr2bfl/fl mice were placed on a 60 kcal% fat diet. Despite similar weight gain, CD11c-Cre+ Fcgr2bfl/fl mice were significantly more glucose intolerant after six weeks. Analysis of white adipose tissue (WAT) demonstrated a two-fold increase in pro-inflammatory AT DCs with increased MHC Class II and CD86. Collectively, these results demonstrate that the absence of FcγRIIb on CD11c+ cells results in increased liver and AT inflammation, influencing atherogenesis and development of glucose intolerance.