Atherosclerosis is usually investigated in murine models with disrupted lipid homeostasis, primarily the ApoE⁻/⁻ and LDLR⁻/⁻ mice. The impact of antigen-presenting cells (APCs) on lipid regulation remains unclear. In our study using a LacZ reporter mouse, we observed an enrichment of CD11c⁺ cells in the aortae of ApoE⁻/⁻ mice. Long-term systemic depletion of wildtype CD11c⁺ cells in bone marrow-transplanted ApoE⁻/⁻ mice led to a significant increase in plaque formation, which correlated with decreased serum ApoE levels.
Analyzing CD11ccre⁺ApoEfl/fl and Albumincre⁺ApoEfl/fl mice, we found that approximately 70% of Serum-ApoE is liver-derived, while about 25% originates from CD11c⁺ cells. Both strains exhibited a significantly higher burden of atherosclerotic plaques compared to cre-negative littermates. Specific deletion of ApoE in CD11c⁺ cells resulted in increased inflammation, as indicated by elevated IL-1β serum levels. Additionally, exposure to acLDL enhanced cholesterol efflux from bone marrow-derived CD11c⁺ cells in vitro.
To assess the atheroprotective potential of human ApoE isoforms in APCs, we transferred ApoE⁻/⁻ mice with bone marrow from mice transgenic for human ApoE2 or ApoE3 or ApoE4. CD11c⁺-specific expression of ApoE2 and ApoE3 but not of ApoE4 isoforms significantly reduced atherosclerotic plaque formation in ApoE⁻/⁻ mice.
For the first time, our findings quantify the contribution of CD11c⁺-derived ApoE and demonstrate that these cells mitigate atherosclerosis through ApoE secretion.
