Intracellular Interleukin-1 Receptor 2 Binding Prevents Cleavage and Activity of Interleukin-1α, Controlling Necrosis-Induced Sterile Inflammation
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Necrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1α (IL-1α) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1α activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1α inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1α. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1α. Full IL-1α activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1α activity postnecrosis and the mechanism allowing conditional release of this blockade.
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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 [189]
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- Authors
- Zheng, Y., Humphry, M., Maguire, J. J., Bennett, M. R., & Clarke, M. C. H.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Clarke, Murray C.H.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 38
- Issue
- 2
- Pages
- 285-295
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3659285
- OpenAlex
- W2038182824
- Cited by
- 205
- References
- 54
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 15 · 2023: 11 · 2022: 18 · 2021: 15 · 2020: 6 · 2019: 14 · 2018: 15 · 2017: 17 · 2016: 18 · 2015: 20 · 2014: 18 · 2013: 22
- FWCI
- 11.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- National Institute for Health and Care Research
- British Heart Foundation (RG/08/009/25841, PG/06/024/20354, FS/13/3/30038, RG04/001, FS/09/005/26845)
- NIHR Cambridge Biomedical Research Centre
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- interleukin-1 alpha, interleukin-1 receptor 2, sterile inflammation, necrosis, caspase-1, calpain, IL-1 receptor 1, damage-associated molecular patterns
- MeSH terms
- Animals, Calpain, Cell Line, Gene Expression Regulation, Humans, Inflammation, Necrosis, Organ Specificity, Protein Binding, Protein Precursors, Signal Transduction, Caspase 1, Mice, Receptors, Interleukin-1 Type II, Interleukin-1alpha, Proteolysis
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