Scavenger receptor class B type I (SR-BI) is an HDL re- ceptor that promotes bidirectional fl ux of free cholesterol between cells and HDL, as well as selective uptake of HDL cholesteryl ester into hepatocytes and steroidogenic cells

Scavenger receptor class B type I (SR-BI) is an HDL receptor that promotes bidirectional fl ux of free cholesterol between cells and HDL, as well as selective uptake of HDL cholesteryl ester into hepatocytes and steroidogenic cells ( 1, 2 ). Single deletion of mouse SR-BI accelerates atherosclerosis, whereas combined deletion of SR-BI and ApoE mimics several features of human coronary disease, including occlusive atherosclerosis, myocardial infarction, and premature death ( 3 ). These anti-atherosclerotic effects are only in part due to hepatic SR-BI regulation of HDL cholesterol metabolism ( 4 ), with mounting evidence supporting independent atheroprotective functions of macrophage SR-BI. Transplantation of SR-BI / bone marrow (BM) into LDLR / mice accelerates atherosclerosis development ( 5 ). Similarly, transplantation of SR-BI / /ApoE / BM into ApoE / mice enhances atherosclerotic lesion formation ( 6 ). The mechanisms by which macrophage SR-BI infl uences atherosclerosis have not been elucidated. Macrophage cell death and the efferocytosis of apoptotic cells are Abstract Macrophage apoptosis and efferocytosis are key determinants of atherosclerotic plaque infl ammation and necrosis. Bone marrow transplantation studies in ApoEand LDLR-defi cient mice revealed that hematopoietic scavenger receptor class B type I (SR-BI) defi ciency results in severely defective efferocytosis in mouse atherosclerotic lesions, resulting in a 17-fold higher ratio of free to macrophageassociated dead cells in lesions containing SR-BI / cells, 5-fold more necrosis, 65.2% less lesional collagen content, nearly 7-fold higher dead cell accumulation, and 2-fold larger lesion area. Hematopoietic SR-BI deletion elicited a maladaptive infl ammatory response [higher interleukin (IL)-1  , IL-6, and TNF; lower IL-10 and transforming growth factor ]. Efferocytosis of apoptotic thymocytes was reduced by 64% in SR-BI / versus WT macrophages, both in vitro and in vivo. In response to apoptotic cells, macrophage SR-BI bound with phosphatidylserine and induced Src phosphorylation and cell membrane recruitment, which led to downstream activation of phosphoinositide 3-kinase (PI3K) and Ras-related C3 botulinum toxin substrate 1 (Rac1) for engulfment and clearance of apoptotic cells, as inhibition of Src decreased PI3K, Rac1-GTP, and efferocytosis in WT cells . Pharmacological inhibition of Rac1 reduced macrophage efferocytosis in a SR-BI-dependent fashion, and activation of Rac1 corrected the defective efferocytosis in SR-BI / macrophages. Thus, defi ciency of macrophage SR-BI promotes defective efferocytosis signaling via the Src/PI3K/Rac1 pathway, resulting in increased plaque size, necrosis, and infl ammation. —Tao, H., P. G. Yancey, V. R. Babaev, J. L. Blakemore, Y. Zhang, L. Ding, S. Fazio, and M. F. Linton. Macrophage SR-BI mediates efferocytosis via Src/ PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. J. Lipid Res. 2015. 56: 1449–1460.