Vascular Smooth Muscle Cell Apoptosis Induces Interleukin-1–Directed Inflammation: Effects of Hyperlipidemia-Mediated Inhibition of Phagocytosis
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Rationale : Atherosclerosis is characterized by lipid accumulation in the vessel wall, inflammation, and both macrophage and vascular smooth muscle cell (VSMC) apoptosis. However, whereas VSMC apoptosis in mice with established atherosclerotic plaques or hyperlipidemia increases serum levels of the proatherogenic cytokines monocyte chemotactic protein (MCP)-1, tumor necrosis factor α, and interleukin (IL)-6, the link between hyperlipidemia, apoptosis and inflammation, and the mechanisms by which apoptotic cells promote inflammation in atherosclerosis are unknown. Objective : To determine whether hyperlipidemia affects apoptotic cell clearance, and identify the molecular pathways downstream of VSMC apoptosis that may promote inflammation. Methods and Results : We find that human VSMCs are potent and efficient phagocytes of apoptotic human VSMCs, but phagocytosis is significantly reduced by oxidized low-density lipoprotein in vitro or hyperlipidemia in vivo. Necrotic human aortic VSMCs release IL-1α, which induces IL-6 and MCP-1 production from viable human VSMCs in vitro. In contrast, secondary necrotic VSMCs release both IL-1α and caspase-activated IL-1β, augmenting IL-6 and MCP-1 production. Conditionally inducing VSMC apoptosis in situ in hyperlipidemic SM22α-hDTR/ApoE −/− mice to levels seen in human plaques increases serum MCP-1, tumor necrosis factor α, and IL-6, which is prevented by blocking IL-1. Conclusions : We conclude that VSMC necrosis releases IL-1α, whereas secondary necrosis of apoptotic VSMCs releases both IL-1α and β. IL-1 from necrotic VSMCs induces the surrounding viable VSMCs to produce proinflammatory cytokines. Thus, failed clearance of apoptotic VSMCs caused by hyperlipidemia in vivo may promote the increased serum cytokines and chronic inflammation associated with atherosclerosis.
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Necrotic VSMCs potently drive inflammation via IL1α due to a lack of IL-1R2 that normally binds and inhibits IL-1α.
“Indeed, necrotic VSMCs potently drive inflammation via IL1α due to a lack of IL-1R2 that normally binds and inhibits IL-1α 133,189 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [133]
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- Authors
- Clarke, M. C. H., Talib, S., Figg, N. L., & Bennett, M. R.
- Affiliations
- University of Cambridge (GB)
- Venue
- Circulation Research
- Published
- 2010-02-05
- Volume
- 106
- Issue
- 2
- Pages
- 363-372
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2071311043
- Cited by
- 216
- References
- 45
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 15 · 2023: 15 · 2022: 22 · 2021: 17 · 2020: 12 · 2019: 14 · 2018: 11 · 2017: 15 · 2016: 10 · 2015: 15 · 2014: 14 · 2013: 8 · 2012: 10
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- British Heart Foundation (PG/06/024/20354, RG04/001, FS/09/005/26845)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- vascular smooth muscle cell apoptosis, atherosclerosis, inflammation, interleukin-1, IL-1α, IL-1β, necrosis, hyperlipidemia, oxidized LDL, efferocytosis, phagocytosis, MCP-1, interleukin-6, TNF-α, inflammatory cytokines
- MeSH terms
- Animals, Apolipoproteins E, Cells, Cultured, Humans, Hyperlipidemias, Immunohistochemistry, Inflammation, Mice, Transgenic, Muscle, Smooth, Vascular, Phagocytosis, Blotting, Western, Interleukin-6, Apoptosis, Mice, Knockout, Chemokine CCL2, Myocytes, Smooth Muscle, Intercellular Signaling Peptides and Proteins, Mice, Interleukin-1alpha, Heparin-binding EGF-like Growth Factor
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