Suppression of NLRX1 in chronic obstructive pulmonary disease

• Published in: The Journal of clinical investigation 2015-06, Vol.125 (6), p.2458-2462
• Main Authors: Kang, Min-Jong, Yoon, Chang Min, Kim, Bo Hye, Lee, Chang-Min, Zhou, Yang, Sauler, Maor, Homer, Rober, Dhamija, Anish, Boffa, Daniel, West, Andrew Phillip, Shadel, Gerald S, Ting, Jenny P, Tedrow, John R, Kaminski, Naftali, Kim, Woo Jin, Lee, Chun Geun, Oh, Yeon-Mok, Elias, Jack A
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Airway management; Animals; Autophagy; Biomedical research; Brief Report; Chronic obstructive lung disease; Chronic obstructive pulmonary disease; DEAD Box Protein 58; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Disease; Disease Models, Animal; Female; Gene expression; Genetic aspects; Health aspects; Humans; Male; Mice; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mortality; Proteins; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - pathology; Pulmonary Disease, Chronic Obstructive - etiology; Pulmonary Disease, Chronic Obstructive - genetics; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - pathology; Quality of life; Receptors, Immunologic; Risk factors; Rodents; Signal Transduction; Smoking; Smoking - adverse effects; Smoking - genetics; Smoking - metabolism; Studies
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI71747

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.