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Publication
Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces
atherosclerotic lesion necrosis.
Authors Tao H, Yancey PG, Babaev VR, Blakemore JL, Zhang Y, Ding L, Fazio S, Linton MF
Submitted By Submitted Externally on 11/3/2015
Status Published
Journal Journal of lipid research
Year 2015
Date Published 8/1/2015
Volume : Pages 56 : 1449 - 60
PubMed Reference 26059978
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)-1ß, IL-6,
and TNF-a lower IL-10 and transforming growth factor ß]. 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.




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