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

• DOI: 10.1084/jem.20180118
• Publication Date: 2018-03-06T13:35:15Z
• Authors: Sharmila Nair; Jeremy P. Huynh; Vicky Lampropoulou; Ekaterina Loginic...; Ekaterina Esaulova; Anshu P. Gounder; Adrianus C.M. Boon; Elizabeth A. Schw...; Tara R. Bradstreet; Brian T. Edelson; Maxim N. Artyomov; Christina L. Stal...; Michael S. Diamond
• Keywords: CD11c

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 regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions Irg1 vivo, we challenged wild-type (WT) Irg1-/- mice with Mycobacterium tuberculosis (Mtb) monitored disease progression. Irg1-/-, but not WT, succumbed rapidly to Mtb, mortality was associated increased infection, inflammation, pathology. Infection LysM-Cre Irg1fl/fl, Mrp8-Cre CD11c-Cre Irg1fl/fl conditional knockout along neutrophil depletion experiments revealed role for LysM+ preventing neutrophil-mediated immunopathology disease. RNA sequencing analyses production temper Mtb-induced responses at transcriptional level. Thus, an regulatory axis modulates curtail lung