Suppression of NLRX1 in chronic obstructive pulmonary disease.
Cigarette smoke (CS) and viruses promote the inflammation and remodeling associated with chronic obstructive pulmonary disease (COPD). The MAVS/RIG-I-like helicase (MAVS/RLH) pathway and inflammasome-dependent innate immune pathways are important mediators of these responses. At baseline, the MAVS/RLH pathway is suppressed, and this inhibition must be reversed to engender tissue effects; however, the mechanisms that mediate activation and repression of the pathway have not been defined. In addition, the regulation and contribution of MAVS/RLH signaling in CS-induced inflammation and remodeling responses and in the development of human COPD remain unaddressed. Here, we demonstrate that expression of NLRX1, which inhibits the MAVS/RLH pathway and regulates other innate immune responses, was markedly decreased in 3 independent cohorts of COPD patients. NLRX1 suppression correlated directly with disease severity and inversely with pulmonary function, quality of life, and prognosis. In murine models, CS inhibited NLRX1, and CS-induced inflammation, alveolar destruction, protease induction, structural cell apoptosis, and inflammasome activation were augmented in NLRX1-deficient animals. Conversely, MAVS deficiency abrogated this CS-induced inflammation and remodeling. Restoration of NLRX1 in CS-exposed animals ameliorated alveolar destruction. These data support a model in which CS-dependent NLRX1 inhibition facilitates MAVS/RHL activation and subsequent inflammation, remodeling, protease, cell death, and inflammasome responses.
Min-Jong
MJ
Kang
Chang Min
CM
Yoon
Bo Hye
BH
Kim
Chang-Min
CM
Lee
Yang
Y
Zhou
Maor
M
Sauler
Rober
R
Homer
Anish
A
Dhamija
Daniel
D
Boffa
Andrew Phillip
AP
West
Gerald S
GS
Shadel
Jenny P
JP
Ting
John R
JR
Tedrow
Naftali
N
Kaminski
Woo Jin
WJ
Kim
Chun Geun
CG
Lee
Yeon-Mok
YM
Oh
Jack A
JA
Elias
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011971:Receptors, Immunologic; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D024101:Mitochondrial Proteins; D011971:Receptors, Immunologic; C512612:MAVS protein, mouse; C505371:MAVS protein, human; C527006:NLRX1 protein, human; C555655:NLRX1 protein, mouse; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse