Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis.

Tao H, Yancey PG, Babaev VR, Blakemore JL, Zhang Y, Ding L, Fazio S, Linton MF
J Lipid Res. 2015 56 (8): 1449-60

PMID: 26059978 · PMCID: PMC4513986 · DOI:10.1194/jlr.M056689

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.

Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (20)

Animals Apoptosis Atherosclerosis CD36 Antigens Cell Survival Collagen Gene Deletion Hematopoiesis Macrophages Mice Mice, Inbred C57BL Necrosis Phagocytosis Phagosomes Phosphatidylinositol 3-Kinases Phosphatidylserines Protein Transport rac1 GTP-Binding Protein Signal Transduction src-Family Kinases

Connections (1)

This publication is referenced by other Labnodes entities:

Links