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

    42 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

      Fingerprint

    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

    Cite this

    Tao, H., Yancey, P. G., Babaev, V. R., Blakemore, J. L., Zhang, Y., Ding, L., Fazio, S., & 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