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Cited by 876Immune Response and InflammationInflammasome and immune disordersInflammation biomarkers and pathways

Identification of a key pathway required for the sterile inflammatory response triggered by dying cells

Chen, Chun-Jen, Kono, Hajime, Golenbock, Douglas, Reed, George, Akira, Shizuo, Rock, Kenneth L·2007·Nature Medicine
DOI 10.1038/nm1603
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Abstract

Dying cells stimulate inflammation, and this response is thought to contribute to the pathogenesis of many diseases. Very little has been known, however, about how cell death triggers inflammation. We found here that the acute neutrophilic inflammatory response to cell injury requires the signaling protein myeloid differentiation primary response gene 88 (Myd88). Analysis of the contribution of Myd88-dependent receptors to this response revealed only a minor reduction in mice doubly deficient in Toll-like receptor 2 (Tlr2) and Tlr4 and normal responses in mice lacking Tlr1, Tlr3, Tlr6, Tlr7, Tlr9, Tlr11 or the interleukin-18 receptor (IL-18R). However, mice lacking IL-1R showed a markedly reduced neutrophilic inflammatory response to dead cells and tissue injury in vivo as well as greatly decreased collateral damage from inflammation. This inflammatory response required IL-1alpha, and IL-1R function was required on non-bone-marrow-derived cells. Notably, the acute monocyte response to cell death, which is thought to be important for tissue repair, was much less dependent on the IL-1R-Myd88 pathway. Also, this pathway was not required for the neutrophil response to a microbial stimulus. These findings suggest that inhibiting the IL-1R-Myd88 pathway in vivo could block the damage from acute inflammation that occurs in response to sterile cell death, and do so in a way that might not compromise tissue repair or host defense against pathogens.

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Crossref · 10.1038/nm1603

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  • In stimulated macrophages, IL-1α is synthesized de novo and can be actively secreted or passively released from apoptotic cells.

    “In stimulated macrophages, IL-1α is synthesized de novo and can be actively secreted (31) or passively released from apoptotic cells (32).”

    From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [32]

  • In a peritoneal model of sterile inflammation, there was no difference between wild-type and HMGB1-deficient necrotic cells in their ability to promote neutrophilic recruitment.

    “However, in a peritoneal model of sterile inflammation, there was no difference between wild-type and HMGb1-deficient necrotic cells in their ability to promote neutrophilic recruitment22.”

    From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [22]

  • Because mice lacking TLR2 and TLR4 have only a slight reduction in the peritoneal inflammatory response to sterile dead cells in vivo, TLR2-TLR4 signalling is not the main mechanism by which intracellular factors induce inflammatory responses to necrotic cell death.

    “because mice lacking TLR2 and TLR4 have only a slight reduction in the peritoneal inflammatory response to sterile dead cells in vivo22, a reasonable conclusion is that TLR2–TLR4 signalling is not the main mechanism by which intracellular factors induce inflammatory responses to necrotic cell death.”

    From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [22]

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Authors
Chen, C.-J., Kono, H., Golenbock, D., Reed, G., Akira, S., & Rock, K. L.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • Research Institute for Microbial Diseases, The University of Osaka (JP)
Corresponding author
Rock, Kenneth L
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2007-06-17
Volume
13
Issue
7
Pages
851-856
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm1603
OpenAlex
W2074213282
Cited by
876
References
33
Citations by year
2026: 13 · 2025: 21 · 2024: 15 · 2023: 22 · 2022: 26 · 2021: 40 · 2020: 30 · 2019: 44 · 2018: 46 · 2017: 55 · 2016: 60 · 2015: 79 · 2014: 51 · 2013: 65 · 2012: 51
FWCI
23.94
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
Funders
  • Yale University
  • National Science Council (NSC95)
  • Kanae Foundation for the Promotion of Medical Science
  • National Institutes of Health (DK32520)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 32520, P30DK032520)
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
sterile inflammation, cell death, MyD88, IL-1 receptor, IL-1α, neutrophilic inflammation, Toll-like receptors, monocyte response, tissue damage, collateral damage, tissue repair
MeSH terms
Animals, Cell Line, Inflammation, Liver, Peroxidase, Oligopeptides, Signal Transduction, Cell Death, Gene Deletion, Receptors, Interleukin-1, Mice, Interleukin-1alpha, Myeloid Differentiation Factor 88, Receptors, Interleukin-18

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