<i>Irg1</i> expression in myeloid cells prevents immunopathology during <i>M. tuberculosis</i> infection

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 <i>Irg1</i>^-/- mice with <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) and monitored disease progression. <i>Irg1</i>^-/-, but not WT, mice succumbed rapidly to <i>Mtb</i>, and mortality was associated with increased infection, inflammation, and pathology. Infection of <i>LysM</i>-Cre <i>Irg1</i>^fl/fl, <i>Mrp8</i>-Cre <i>Irg1</i>^fl/fl, and <i>CD11c</i>-Cre <i>Irg1</i>^fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in <i>LysM</i>⁺ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper <i>Mtb</i>-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail <i>Mtb</i>-induced lung disease.