Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade

Journal article

Ying Wang, V. Nanda, D. Direnzo, Jianqin Ye, Sophia Xiao, Y. Kojima, K. Howe, K. Jarr, Alyssa M. Flores, P. Tsantilas, N. Tsao, Abhiram S. Rao, Alexandra A. C. Newman, Anne V. Eberhard, J. Priest, A. Ruusalepp, G. Pasterkamp, L. Maegdefessel, Clint L. Miller, L. Lind, Simon Koplev, J. Björkegren, G. Owens, E. Ingelsson, I. Weissman, N. Leeper
Proceedings of the National Academy of Sciences of the United States of America, 2020

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APA Click to copy
Wang, Y., Nanda, V., Direnzo, D., Ye, J., Xiao, S., Kojima, Y., … Leeper, N. (2020). Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade. Proceedings of the National Academy of Sciences of the United States of America.

Chicago/Turabian Click to copy
Wang, Ying, V. Nanda, D. Direnzo, Jianqin Ye, Sophia Xiao, Y. Kojima, K. Howe, et al. “Clonally Expanding Smooth Muscle Cells Promote Atherosclerosis by Escaping Efferocytosis and Activating the Complement Cascade.” Proceedings of the National Academy of Sciences of the United States of America (2020).

MLA Click to copy
Wang, Ying, et al. “Clonally Expanding Smooth Muscle Cells Promote Atherosclerosis by Escaping Efferocytosis and Activating the Complement Cascade.” Proceedings of the National Academy of Sciences of the United States of America, 2020.

BibTeX Click to copy

@article{ying2020a,
  title = {Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade},
  year = {2020},
  journal = {Proceedings of the National Academy of Sciences of the United States of America},
  author = {Wang, Ying and Nanda, V. and Direnzo, D. and Ye, Jianqin and Xiao, Sophia and Kojima, Y. and Howe, K. and Jarr, K. and Flores, Alyssa M. and Tsantilas, P. and Tsao, N. and Rao, Abhiram S. and Newman, Alexandra A. C. and Eberhard, Anne V. and Priest, J. and Ruusalepp, A. and Pasterkamp, G. and Maegdefessel, L. and Miller, Clint L. and Lind, L. and Koplev, Simon and Björkegren, J. and Owens, G. and Ingelsson, E. and Weissman, I. and Leeper, N.}
}

Abstract

Significance Cardiovascular disease remains the world’s leading killer, despite the widespread use of cholesterol-lowering medicines. Recent studies suggest a portion of this residual risk may result from the clonal expansion of cells within the atherosclerotic plaques of diseased blood vessels. How these cells promote inflammation and whether they can be therapeutically targeted remain unclear. The current study suggests that clonally expanding cells may cause disease by triggering the complement cascade while evading immune surveillance. However, these cells also appear to be susceptible to therapies that reactivate phagocytic clearance pathways, suggesting a potential treatment approach for heart disease similar to current oncology efforts directed against the cancer stem cell. 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” 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 opsonin-sensing 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.