Female CD11c-Cre + Fcgr2b fl/fl recipients have larger plaques than control mice. • Male CD11c-Cre + Fcgr2b fl/fl recipients have smaller plaques than control mice. • CD11c-specific FcγRIIb alters hepatic inflammation differently in males and females. • A CD11c-conditional FcγRIIb knockout decreases serum lipoproteins in both sexes. • Liver lipid synthesis and handling are altered in CD11c-Cre + Fcgr2b fl/fl recipients. A B S T R A C TBackground and aims: Circulating levels of oxidized lipoprotein (oxLDL) correlate with myocardial infarction risk and atherosclerosis severity. Our previous study demonstrates that oxLDL immune complexes (oxLDL-ICs) can signal through FcγRs on bone marrow-derived dendritic cells (BMDCs) and enhance their activation and inflammatory cytokine secretion. While global FcγR −/− studies have shown that activating FcγRs are proatherogenic, the role of the inhibitory FcγRIIb is unclear. We sought to determine the role of DC-specific FcγRIIb in atherosclerosis. Methods: Bone marrow chimeras were generated by rescuing lethally irradiated Ldlr −/− mice with hematopoietic cells from littermate CD11c-Cre + or CD11c-Cre -Fcgr2b fl/fl donors. Four weeks following transplant, recipients were placed on a Western diet for eight weeks. Various tissues and organs were analyzed for differences in inflammation. Results: Quantitation of atherosclerosis in the proximal aorta demonstrated a 58% increase in female CD11c-Cre + Fcgr2b fl/fl recipients, but a surprising 44% decrease in male recipients. Hepatic cholesterol and triglycerides were increased in female CD11c-Cre + Fcgr2b fl/fl recipients. This was associated with an increase in CD36 and MHC Class II expression on hepatic CD11c + CD11b + DCs in female livers. In contrast, male CD11c-Cre + Fcgr2b fl/ fl recipients had decreased hepatic lipids with a corresponding decrease in CD36 and MHC Class II expression on CD11c + cells. Interestingly, both sexes of CD11c-Cre + Fcgr2b fl/fl recipients had significant decreases in serum cholesterol and TGs with corresponding decreases in liver Fasn transcripts. Conclusions: The absence of FcγRIIb expression on CD11c + cells results in sex-dependent alteration in liver inflammation influencing atherogenesis and sex-independent modulation of serum cholesterol and TGs.

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.