Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade
Wang, Ying; Nanda, Vivek; Direnzo, Daniel; Ye, Jianqin; Xiao, Sophia; Kojima, Yoko; Howe, Kathryn L.; Jarr, Kai Uwe; Flores, Alyssa M.; Tsantilas, Pavlos; Tsao, Noah; Rao, Abhiram; Newman, Alexandra A.C.; Eberhard, Anne V.; Priest, James R.; Ruusalepp, Arno; Pasterkamp, Gerard; Maegdefessel, Lars; Miller, Clint L.; Lind, Lars; Koplev, Simon; Björkegren, Johan L.M.; Owens, Gary K.; Ingelsson, Erik; Weissman, Irving L.; Leeper, Nicholas J.
(2020) Proceedings of the National Academy of Sciences of the United States of America, volume 117, issue 27, pp. 15818 - 15826
(Article)
Abstract
Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated"
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vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsoninsensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.
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Keywords: Atherosclerosis, CD47, Clonality, Efferocytosis, Smooth muscle cells, General
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: ACKNOWLEDGMENTS. This study was supported by the NIH (R35 HL144475, R01 HL125224, and R01 HL123370 to N.J.L.; R01 HL125863 to J.L.M.B.), American Heart Association (19EIA34770065 to N.J.L.; 18POST34030084 to Y.W.; A14SFRN20840000 to J.L.M.B.), Swedish Research Council and Heart Lung Foundation (2018-02529 and 20170265 to J.L.M.B.), Deutsche For-schungsgemeinschaft (JA 2869/1-1:1 to K.-U.J.), and Fondation Leducq (“PlaqOmics” 18CVD02 to N.J.L., J.L.M.B., C.L.M., G.P., and G.K.O.). We acknowledge Stefan Gustafsson, Tom Quertermous, Robert Wirka, and Milos Pjanic for critical input on the manuscript, Zhichao Ni (Qingbo Xu lab, King’s College) for advice on Sca1+ SMC culture, and the Stanford Shared FACS Facility (via NIH S10 Shared Instrument Grant S10RR027431-01) and Cell Sciences Imaging Facility for access to core facilities. Funding Information: This study was supported by the NIH (R35 HL144475, R01 HL125224, and R01 HL123370 to N.J.L.; R01 HL125863 to J.L.M.B.), American Heart Association (19EIA34770065 to N.J.L.; 18POST34030084 to Y.W.; A14SFRN20840000 to J.L.M.B.), Swedish Research Council and Heart Lung Foundation (2018-02529 and 20170265 to J.L.M.B.), Deutsche Forschungsgemeinschaft (JA 2869/1-1:1 to K.-U.J.), and Fondation Leducq ("PlaqOmics" 18CVD02 to N.J.L., J.L.M.B., C.L.M., G.P., and G.K.O.). We acknowledge Stefan Gustafsson, Tom Quertermous, Robert Wirka, and Milos Pjanic for critical input on the manuscript, Zhichao Ni (Qingbo Xu lab, King's College) for advice on Sca1+ SMC culture, and the Stanford Shared FACS Facility (via NIH S10 Shared Instrument Grant S10RR027431-01) and Cell Sciences Imaging Facility for access to core facilities. Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.
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