Suppression of NLRX1 in chronic obstructive pulmonary disease

We extracted the mRNAs from fresh-frozen lung tissues from the 7 controls and 36 patients with COPD in the NIH-sponsored Lung Tissue Research Consortium (LTRC) cohort. The latter contained 6, 10, 10, and 10 specimens from Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1, 2, 3, and 4 individuals, respectively (Supplemental Table Real-time RT-PCR analysis demonstrated that the levels of mRNA encoding NLRX1 were significantly decreased in patients with advanced stages of COPD (Figure Western blot evaluations demonstrated that NLRX1 protein expression was significantly decreased in patients with advanced stages of COPD (Supplemental Figure NLRX1 expression correlated significantly with the patient's forced expiratory volume in 1 second (FEV 1 ; % predicted), an indicator of 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.