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

Huan Tao, Patricia G. Yancey, Vladimir R. Babaev, John L. Blakemore, Youmin Zhang, Lei Ding, Sergio Fazio, Macrae F. Linton

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Macrophage apoptosis and efferocytosis are key determinants of atherosclerotic plaque infl ammation and necrosis. Bone marrow transplantation studies in ApoE- and 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 β , 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, 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.

Original languageEnglish (US)
Pages (from-to)1449-1460
Number of pages12
JournalJournal of lipid research
Volume56
Issue number8
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

Keywords

  • Apoptosis
  • Atherosclerosis
  • Infl ammation
  • Phosphoinositide 3-kinase
  • Ras-related C3 botulinum toxin substrate 1
  • Scavenger receptor class B type I
  • Src

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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