Targeted invalidation of SR-B1 in macrophages reduces macrophage apoptosis and accelerates atherosclerosis

SR-B1 is a cholesterol transporter that exerts anti-atherogenic properties in liver and peripheral tissues in mice. Bone marrow (BM) transfer studies suggested an atheroprotective role in cells of haematopoietic origin. Here, we addressed the specific contribution of SR-B1 in the monocyte/macrophage.

We generated mice deficient for SR-B1 in monocytes/macrophages (Lysm-Cre × SR-B1^f/f) and transplanted their BM into Ldlr^−/− mice. Fed a cholesterol-rich diet, these mice displayed accelerated aortic atherosclerosis characterized by larger macrophage-rich areas and decreased macrophage apoptosis compared with SR-B1^f/f transplanted controls. These findings were reproduced in BM transfer studies using another atherogenic mouse recipient (SR-B1 KO^liver × Cholesteryl Ester Transfer Protein). Haematopoietic reconstitution with SR-B1^−/− BM conducted in parallel generated similar results to those obtained with Lysm-Cre × SR-B1^f/f BM; thus suggesting that among haematopoietic-derived cells, SR-B1 exerts its atheroprotective role primarily in monocytes/macrophages. Consistent with our in vivo data, free cholesterol (FC)-induced apoptosis of macrophages was diminished in the absence of SR-B1. This effect could not be attributed to differential cellular cholesterol loading. However, we observed that expression of apoptosis inhibitor of macrophage (AIM) was induced in SR-B1-deficient macrophages, and notably upon FC-loading. Furthermore, we demonstrated that macrophages were protected from FC-induced apoptosis by AIM. Finally, AIM protein was found more present within the macrophage-rich area of the atherosclerotic lesions of SR-B1-deficient macrophages than controls.

Our findings suggest that macrophage SR-B1 plays a role in plaque growth by controlling macrophage apoptosis in an AIM-dependent manner.