Abstract 17224: Macrophage Expressed CD36 Promotes Plaque Vulnerability in Atherosclerosis

Abstract

Introduction: Atherosclerosis is characterised by a chronic lipid-driven inflammation that accounts for the majority of deaths worldwide. CD36 is an immunoregulatory scavenger receptor at the interface of lipid metabolism and inflammation that is critically involved in atherogenesis. However, due to the lack of cell-specific animal models the exact role of CD36 on macrophages in atherosclerosis remains unknown to date. Research Question: Here, we aimed to study the role of macrophage expressed CD36 in atherogenesis. Methods: To screen for a potential role of macrophage expressed CD36 in atherosclerosis we assessed CD36 gene expression across different leukocyte populations in scRNAseq data from atherosclerotic LDLR-/- mice. To evaluate the role of macrophage expressed CD36 in atherogenesis, we generated tamoxifen inducible macrophage (CX3CR1)-specific CD36-deficient mice on a LDLR-/- background. To interrogate a potential role of CD36 in human atherosclerosis, human atherosclerotic plaques were studied by scRNAseq. Results: Analysis of murine scRNAseq data identified macrophages as the main CD36 expressing cell type. In line, CD36 protein expression in aortic cell suspensions from LDLR-/- mice was significantly higher in macrophages compared to B and T cells as assessed by flow cytometry. Notably, macrophage-specific CD36 deficiency substantially reduced lesional necrotic core area after 16 weeks of high cholesterol diet feeding indicating ameliorated plaque vulnerability. In vitro, macrophage-specific CD36 deficiency reduced ROS production and oxLDL uptake. Similar to our observations in mice, cellular CD36 expression was highest in human macrophages/monocytes. Pathway analysis revealed that CD36-expressing macrophages exhibited a more pro-inflammatory gene signature than CD36-negative macrophages. Finally, unstable carotid plaques displayed a significantly higher CD36 expression compared to stable lesions. Conclusion: All in all, our data indicates a pro-inflammatory role of macrophage expressed CD36 in murine and human atherosclerosis. These findings suggest that targeting CD36 on macrophages may represent a potential target for anti-atherosclerotic therapy.