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J Exp Med. 2018 Apr 2;215(4):1035-1045. doi: 10.1084/jem.20180118. Epub 2018 Mar 6.

Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection.

Author information

1
Department of Medicine, Washington University School of Medicine, St. Louis, MO.
2
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO.
3
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO.
4
Computer Technologies Department, ITMO University, Saint Petersburg, Russia.
5
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO stallings@wustl.edu.
6
Department of Medicine, Washington University School of Medicine, St. Louis, MO diamond@wusm.wustl.edu.
7
The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO.

Abstract

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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