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

26 Citations (Scopus)

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

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CD36 Antigens
Scavenger Receptors
1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Necrosis
Phosphotransferases
Macrophages
rac1 GTP-Binding Protein
Chemical activation
Cells
Phosphorylation
Phosphatidylserines
Transforming Growth Factors
Apolipoproteins E
Atherosclerotic Plaques
Thymocytes
Cell membranes
Guanosine Triphosphate
Bone Marrow Transplantation
Interleukin-1

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
  • Cell Biology
  • Endocrinology

Cite this

Tao, H., Yancey, P. G., Babaev, V. R., Blakemore, J. L., Zhang, Y., Ding, L., ... Linton, M. F. (2015). Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. Journal of Lipid Research, 56(8), 1449-1460. https://doi.org/10.1194/jlr.M056689

Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. / Tao, Huan; Yancey, Patricia G.; Babaev, Vladimir R.; Blakemore, John L.; Zhang, Youmin; Ding, Lei; Fazio, Sergio; Linton, Macrae F.

In: Journal of Lipid Research, Vol. 56, No. 8, 01.08.2015, p. 1449-1460.

Research output: Contribution to journalArticle

Tao, H, Yancey, PG, Babaev, VR, Blakemore, JL, Zhang, Y, Ding, L, Fazio, S & Linton, MF 2015, 'Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis', Journal of Lipid Research, vol. 56, no. 8, pp. 1449-1460. https://doi.org/10.1194/jlr.M056689
Tao, Huan ; Yancey, Patricia G. ; Babaev, Vladimir R. ; Blakemore, John L. ; Zhang, Youmin ; Ding, Lei ; Fazio, Sergio ; Linton, Macrae F. / Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. In: Journal of Lipid Research. 2015 ; Vol. 56, No. 8. pp. 1449-1460.
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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.",
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