Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection
Open accessAbstract
Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1−/− mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1−/−, but not WT, mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, Mrp8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb-induced lung disease.
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IRG1 mediates the immunomodulatory effects of CORM2-induced HMOX1 on TNF-α production in LPS-activated macrophages and in a murine endotoxin shock model.
“IRG1 has also been shown to mediate the immunomodulatory effects of CO releasing molecule 2 (CORM2)-induced HMOX1 on TNF-αproduction in both LPS-activated macrophages and in a murine endotoxin shock model69”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [69]
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- Authors
- Nair, S., Huynh, J. P., Lampropoulou, V., Loginicheva, E., Esaulova, E., Gounder, A. P., Boon, A. C. M., Schwarzkopf, E. A., Bradstreet, T. R., Edelson, B. T., Artyomov, M. N., Stallings, C. L., & Diamond, M. S.
- Affiliations
- Washington University in St. Louis (US)
- ITMO University (RU)
- Corresponding author
- Stallings, Christina L.
- Diamond, Michael S.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2018-03-06
- Volume
- 215
- Issue
- 4
- Pages
- 1035-1045
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC5881474
- OpenAlex
- W2790085444
- Cited by
- 280
- References
- 21
- Citations by year
- 2026: 29 · 2025: 35 · 2024: 44 · 2023: 40 · 2022: 39 · 2021: 41 · 2020: 27 · 2019: 17 · 2018: 8
- FWCI
- 17.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- National Institutes of Health (R01 AI04972, R01 AI118938, R01 AI125618)
- Arnold and Mabel Beckman Foundation
- Burroughs Wellcome Fund
- NIH (S10 RR027552)
- Deutsche Forschungsgemeinschaft
- The National Science Foundation (DGE-1143954)
- government of the Russian Federation (074-U01)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- IRG1, itaconate, Mycobacterium tuberculosis, tuberculosis, myeloid cells, neutrophils, immunopathology, inflammation, conditional knockout mice, lung disease, transcriptional regulation, reactive oxygen species, cytokine production
- MeSH terms
- Animals, Female, Hydro-Lyases, Inflammation, Lung Diseases, Male, Mice, Inbred C57BL, Mycobacterium tuberculosis, Neutrophils, Succinates, Transcription, Genetic, Tuberculosis, Gene Expression, Cytokines, Reactive Oxygen Species, Mice, Knockout, Disease Progression, Myeloid Cells, Mice
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