FcγRIIb on CD11c Cells Modulates Serum Cholesterol and Triglyceride Levels and Differentially Affects Atherosclerosis in Male and Female Ldlr Mice

Background 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-CreFcgr2b 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-CreFcgr2b recipients, but a surprising 44% decrease in male recipients. Hepatic cholesterol and triglycerides were increased in female CD11c-CreFcgr2b recipients. This was associated with an increase in CD36 and MHC Class II expression on hepatic CD11cCD11b DCs in female livers. In contrast, male CD11c-CreFcgr2b recipients had decreased hepatic lipids with a corresponding decrease in CD36 and MHC Class II expression on CD11c cells. Interestingly, both sexes of CD11c-CreFcgr2b 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.