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

Abstract

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.

Deletion of Ppard in CD11c + cells attenuates atherosclerosis in ApoE knockout mice

“…Previous studies showed that DCs regulate cholesterol metabolism by affecting lipid absorption in the small instestine, 35 or modulating lipid uptake in hepatic DCs through CD36 and further regulating hepatic triglyceride storage. 36 In our hands, although PPARδ is known to regulate fatty acid metabolism in many types of cells, we found that cholesterol and triglyceride levels were similar between Ppard DC-WT but not Ppard DC-KO mice. At this stage, we cannot exclude the involvement of CD36 and CD40 in CD11c + cells from other organs involved in lipid metabolism (eg, liver and intestine).…”

T cells expressing the lupus susceptibility allele Pbx1d enhance autoimmunity and atherosclerosis in dyslipidemic mice

“…Plates were washed and OptEIA TMB substrate (BD Biosciences) was added. Plates were developed for 10 minutes prior to quenching with 2 M HCl and read at 450 nM as previously described (62). Triglycerides and cholesterol were measured using a commercially available kit (Raichem), and LDL and HDL were measured by HDL and LDL/VLDL Quantitation Kit (MilliporeSigma).…”

Pathophysiology of Atherosclerotic Plaque Development-Contemporary Experience and New Directions in Research

“…Regarding B lymphocytes, an investigation of atherosclerotic-prone mice with an attenuated B lymphocyte-induced maturation protein 1 (Blimp-1) gene responsible for B-cell maturation revealed an important pro-atherogenic role of these cells and IgG antibodies [26]. Other investigations highlighted the role of immunoglobulins and their receptors, i.e., IgE and FcεR1, in macrophage polarization towards proinflammatory M1 phenotype, and also highlighted the role of FcγRIIb localized on dendritic cells in sexdependent differences in the mouse model of atherogenesis [27,28]. In contrast, studies on Th17 lymphocytes provided conflicting results, although an investigation of ApoE -/mice has revealed increased Th17 lymphocytes among splenocytes in animals with ruptured plaque (induced by LPS and phenylephrine) and increased IL-17 levels within the plaque itself, suggesting a role of this subset of lymphocytes in the plaque rupture [29,30].…”