FcγRIIb on CD11c⁺ cells modulates serum cholesterol and triglyceride levels and differentially affects atherosclerosis in male and female Ldlr^-/- mice.

ABSTRACT:

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-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.

SUBMITTER: Marvin J 

PROVIDER: S-EPMC8086422 | biostudies-literature |

REPOSITORIES: biostudies-literature