Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages
Open accessAbstract
Significance: Although it has long been known that inflammatory immune responses are associated with death of cells through necrosis, the mechanisms controlling this process are not yet well understood. Recently a type of programmed inflammatory cell death, necroptosis, has been discovered. In this paper we reveal previously unidentified molecular mechanisms that operate to induce this form of cell death. Our results indicate that in order to undergo necroptosis, immune cells must produce and receive signals from the key immune regulator, interferon. Such interferon-dependent necroptosis of immune cells drives acute inflammatory pathology in a mouse model of sepsis. This work highlights the intimate connection between cell death and inflammation, and may lead to new understanding and treatment of inflammatory pathologies.
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IFNAR1 and IFNGR1 appear to have pro-necroptotic functions.
“In this context, IFN alpha and beta receptor subunit 1 (IFNAR1) and IFN gamma receptor 1 (IFNGR1) also appear to have pro-necroptotic functions [520–523].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [523]
Ifnar1−/− macrophages are resistant to RCD induced by LPS or polyI:C in context of caspase inhibition, which would otherwise trigger necroptotic process relying on TRIF and tonic ISGF3 signaling.
“Thus, Ifnar1−/− macrophages are resistant to RCD induced by LPS or polyI:C in the context of caspase inhibition, which would otherwise trigger a necroptotic process relying on TRIF and tonic IFN-stimulated gene factor 3 (ISGF3) signaling [523].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [523]
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Cites
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- Authors
- McComb, S., Cessford, E., Alturki, N. A., Joseph, J., Shutinoski, B., Startek, J. B., Gamero, A. M., Mossman, K. L., & Sad, S.
- Affiliations
- University of Ottawa (CA)
- Temple University (US)
- McMaster University (CA)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-07-21
- Volume
- 111
- Issue
- 31
- Pages
- E3206-13
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4128105
- OpenAlex
- W2092585655
- Cited by
- 190
- References
- 5
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 20 · 2023: 18 · 2022: 18 · 2021: 13 · 2020: 18 · 2019: 12 · 2018: 20 · 2017: 17 · 2016: 24 · 2015: 10 · 2014: 1
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Funders
- Genentech
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- type I interferon signaling, necroptosis, ISGF3, macrophages, IFNAR1, interferon-beta, STAT1, STAT2, IRF9, TRIF, inflammation, innate immunity
- MeSH terms
- Animals, Enzyme Activation, Inflammation, Interferon Type I, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Models, Biological, Necrosis, Oligopeptides, Poly I-C, Tumor Necrosis Factor-alpha, Signal Transduction, Apoptosis, Interferon-Stimulated Gene Factor 3, gamma Subunit, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Receptor, Interferon alpha-beta
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