TY - JOUR
T1 - Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection
AU - Nair, Sharmila
AU - Huynh, Jeremy P.
AU - Lampropoulou, Vicky
AU - Loginicheva, Ekaterina
AU - Esaulova, Ekaterina
AU - Gounder, Anshu P.
AU - Boon, Adrianus C.M.
AU - Schwarzkopf, Elizabeth A.
AU - Bradstreet, Tara R.
AU - Edelson, Brian T.
AU - Artyomov, Maxim N.
AU - Stallings, Christina L.
AU - Diamond, Michael S.
N1 - Funding Information:
National Institutes of Health (NIH) grants R01 AI04972 (to M.S. Diamond), R01 AI118938 (to A.C.M. Boon), R01 AI125618 (to M.N. Artyomov), a Beckman Young Investigator Award from the Arnold and Mabel Beckman Foundation (to C.L. Stallings), a Burroughs Wellcome Fund Investigator Award (to C.L. Stallings), a Career Award for Medical Scientists from the Burroughs Wellcome Fund (to B.T. Edelson), and the NIH Shared Instrumentation Grant (S10 RR027552) supported this study. The Deutsche Forschungsgemeinschaft supported S. Nair. The National Science Foundation Graduate Research Fellowship Program (DGE-1143954) supported J.P. Huynh and A. Gounder. The government of the Russian Federation, grant 074-U01, supported E. Esaulova
Publisher Copyright:
© 2018 Nair et al.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044828154&partnerID=8YFLogxK
U2 - 10.1084/jem.20180118
DO - 10.1084/jem.20180118
M3 - Article
C2 - 29511063
AN - SCOPUS:85044828154
VL - 215
SP - 1035
EP - 1045
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -