Cutting Edge: Critical Role for Mesothelial Cells in Necrosis-Induced Inflammation through the Recognition of IL-1α Released from Dying Cells
Open accessAbstract
Endogenous danger signals released from necrotic cells are thought to be sensed by phagocytes leading to secretion of IL-1α and neutrophilic recruitment. However, the mechanisms for IL-1α production and IL-1α-mediated sterile inflammation remain poorly understood. We report here that necrotic cell extracts elicited little secretion of CXCL1 and IL-6 from macrophages but robust production in mesothelial cells. The induction of CXCL1 as well as activation of NF-κB and MAPKs by cytosolic extracts required the presence of IL-1α in the necrotic cell. Conversely, expression of IL-1R and MyD88 but not IL-1α, RICK, TLR2, TLR4, TRIF, or inflammasome components in mesothelial cells was critical for the production of CXCL1. Furthermore, IL-1α was critical to induce the recruitment of neutrophils in the peritoneal cavity via CXCR2. These studies show that IL-1α is a key danger signal released from necrotic cells to trigger CXCL1 secretion and recruitment of neutrophils via IL-1R/MyD88 on neighboring mesothelial cells.
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Intracellular stores of biologically active pro-inflammatory cytokines and chemokines, such as IL-1α and IL-33, may be released by necrotic cells.
“Similarly, in addition to intracellular molecules, intracellular stores of biologically active pro-inflammatory cytokines and chemokines, such as IL-1α15 and IL-33 (REF. 16), may be released by necrotic cells.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [15]
IL-1α released by necrotic cells was crucial for the production of CXCL1, which recruits neutrophils, by non-haematopoietic cells such as mesothelial cells.
“Subsequently, it was shown that IL-1α released by necrotic cells was crucial for the production of CXCL1, which recruits neutrophils, by non-haematopoietic cells such as mesothelial cells15.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [15]
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- Authors
- Eigenbrod, T., Park, J.-H., Harder, J., Iwakura, Y., & Núñez, G.
- Affiliations
- University of Michigan (US)
- Institute of Medical Science, The University of Tokyo (JP)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-12
- Volume
- 181
- Issue
- 12
- Pages
- 8194-8198
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2762646
- OpenAlex
- W1532188080
- Cited by
- 228
- References
- 27
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 10 · 2022: 10 · 2021: 9 · 2020: 14 · 2019: 12 · 2018: 8 · 2017: 10 · 2016: 16 · 2015: 24 · 2014: 14 · 2013: 22 · 2012: 20
- FWCI
- 6.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Amgen
- University of Michigan
- National Institute of Allergy and Infectious Diseases (AI 064748, AI063331, R56AI063331, R01AI064748, R01AI063331, R37AI063331)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR052756)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- mesothelial cells, necrosis, sterile inflammation, IL-1α, damage-associated molecular patterns, CXCL1, neutrophil recruitment, CXCR2, MyD88, IL-1 receptor, NF-κB, MAPK signaling, peritoneal cavity, macrophages
- MeSH terms
- Animals, Cytosol, Epithelium, Liver, Mice, Inbred C57BL, Necrosis, Peritoneal Cavity, Interleukin-6, Macrophages, Peritoneal, Mice, Knockout, Inflammation Mediators, Neutrophil Infiltration, Mice, Interleukin-1alpha, Chemokine CXCL1
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