Suppression of NLRX1 in chronic obstructive pulmonary disease.
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abstract
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.
Kang, M., Yoon, C. M., Kim, B. H., Lee, C., Zhou, Y., Sauler, M., ... Elias, J. A.
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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
