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)-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.
Highlights
Macrophage apoptosis and efferocytosis are key determinants of atherosclerotic plaque inflammation and necrosis
In vivo examination of the phagocytosis of CFDA-carboxyfluorescein diacetate (SE)-labeled apoptotic thymocytes by macrophages in the peritoneal cavity of LDLRϪ/Ϫ mice reconstituted with WT, SR-BIϪ/Ϫ, ApoEϪ/Ϫ, and DKO bone marrow (BM) (Fig. 1C, D) showed that efferocytosis of apoptotic cells was reduced by 47.4% (P < 0.01), 29.1% (P < 0.05), and 66.7% (P < 0.001) in SR-BIϪ/Ϫ, ApoEϪ/Ϫ, and DKO macrophages, respectively
Deletion of macrophage scavenger receptor class B type I (SR-BI) enhances inflammation As defective phagocytosis of apoptotic cells results in secondary cellular necrosis and maladaptive inflammation, we examined the effects of SR-BI deficiency on inflammation in vitro and in vivo
Summary
Macrophage apoptosis and efferocytosis are key determinants of atherosclerotic plaque inflammation and necrosis. Single deletion of mouse SR-BI accelerates atherosclerosis, whereas combined deletion of SR-BI and ApoE mimics several features of human coronary disease, including occlusive atherosclerosis, myocardial infarction, and premature death [3] These anti-atherosclerotic effects are only in part due to hepatic SR-BI regulation of HDL cholesterol metabolism [4], with mounting evidence supporting independent atheroprotective functions of macrophage SR-BI. Macrophage cell death and the efferocytosis of apoptotic cells are Abbreviations: BM, bone marrow; CFDA SE, carboxyfluorescein diacetate, succinimidyl ester; GST, glutathione S-transferase; GULP, engulfment adaptor PTB domain; H and E, hematoxylin and eosin; HMGB1, high-mobility group protein B1; IL, interleukin; LRP1, LDL receptor-related protein 1; MCP-1, monocyte chemotactic protein 1; MMP-9, matrix metaolloproteinase 9; NF-B, nuclear factor-B; PI3K, phosphoinositide 3-kinase; PS, phosphatidylserine; Rac, Ras-related C3 botulinum toxin substrate 1; SR-BI, scavenger receptor class B type I; Src, proto-oncogene tyrosine-protein kinase Src; TGF-, transforming growth factor ; TUNEL, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling; TMR, tetramethylrhodamine
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have