CD36 Expression on Macrophages Drives Plaque Vulnerability In Atherosclerosis

Mark Colin Gissler (Freiburg im Breisgau)1, T. Mwinyella (Freiburg im Breisgau)1, H. Horstmann (Freiburg im Breisgau)1, T. Marchini (Freiburg im Breisgau)1, D. Westermann (Freiburg im Breisgau)1, D. Wolf (Freiburg im Breisgau)1

1Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg im Breisgau, Deutschland


Background: Accumulation of oxidized low density lipoprotein (oxLDL) particles within the vessel wall represents the central driver of atherogenesis and concomitant vascular inflammation. Accumulating oxLDL is taken up by macrophages via scavenger receptors and subsequently promotes foam cell formation, atherosclerotic disease progression and plaque destabilisation. CD36 is an immunoregulatory scavenger receptor at the interface of lipid metabolism and inflammation that has been implicated in macrophage lipid uptake and foam cell formation in vitro. However, due to the lack of cell-specific in vivo models the exact role of CD36 on macrophages in atherosclerosis remains not sufficiently defined to date. In this context we here aimed to clarify the role of macrophage expressed CD36 in atherogenesis in a conditional knockout mouse model and complementing clinical study cohorts.


Approach & Results: 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. Here, we 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 in flow cytometry. Integration of ScRNA-Seq datasets from LDLR-/- mice on chow diet or different durations of HFD revealed that under experimental diet and thereby induction of atherogenesis CD36 is mostly expressed by foamy macrophages. Notably, macrophage-specific CD36 deficiency substantially reduced oxLDL uptake and ROS production. Furthermore, lesional necrotic core area was reduced in mice with macrophage-specific CD36 deficiency after 16 weeks of high cholesterol diet feeding indicating ameliorated plaque vulnerability. 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 human plaques displayed a significantly higher CD36 expression compared to stable lesions indicating that CD36 expression associates with plaque vulnerability in humans. In line, in patients undergoing carotid endarterectomy, CD36 expression was significantly associated with a high severity of symptoms at the time of inclusion and the occurrence of major adverse cardiovascular events in 3 years of follow-up.


Conclusion: All in all, our data indicate a pro-inflammatory role of macrophage expressed CD36 in murine and human atherosclerotic lesions. Our findings suggest that targeting CD36 on macrophages may represent a potential target against lipid-driven inflammation in atherosclerosis.


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