title: Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis.
abstract: Macrophage apoptosis and efferocytosis are key determinants of atherosclerotic plaque inflammation and necrosis. Bone marrow transplantation studies in ApoE- and LDLR-deficient mice revealed that hematopoietic scavenger receptor class B type I (SR-BI) deficiency results in severely defective efferocytosis in mouse atherosclerotic lesions, resulting in a 17-fold higher ratio of free to macrophage-associated 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 inflammatory response [higher interleukin (IL)-1β, IL-6, and TNF-α lower IL-10 and transforming growth factor β]. 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, deficiency of macrophage SR-BI promotes defective efferocytosis signaling via the Src/PI3K/Rac1 pathway, resulting in increased plaque size, necrosis, and inflammation.
authors.affiliation: Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Huan
authors.initials: H
authors.lastname: Tao
authors.affiliation: Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Yancey
authors.affiliation: Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.affiliation: Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: John L
authors.initials: JL
authors.lastname: Blakemore
authors.affiliation: Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Youmin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Medicine, Physiology, and Pharmacology, Center of Preventive Cardiology, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.affiliation: Department of Medicine, Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D017353:Gene Deletion; D006410:Hematopoiesis; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D010718:Phosphatidylserines; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D020830:rac1 GTP-Binding Protein
keywords: Ras-related C3 botulinum toxin substrate 1; Src; apoptosis; atherosclerosis; inflammation; phosphoinositide 3-kinase; scavenger receptor class B type I