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Suppression of NLRX1 in chronic obstructive pulmonary disease
Min-Jong Kang, … , Yeon-Mok Oh, Jack A. Elias
Min-Jong Kang, … , Yeon-Mok Oh, Jack A. Elias
Published May 4, 2015
Citation Information: J Clin Invest. 2015;125(6):2458-2462. https://doi.org/10.1172/JCI71747.
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Brief Report Pulmonology Article has an altmetric score of 47

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.

Authors

Min-Jong Kang, Chang Min Yoon, Bo Hye Kim, Chang-Min Lee, Yang Zhou, Maor Sauler, Rober Homer, Anish Dhamija, Daniel Boffa, Andrew Phillip West, Gerald S. Shadel, Jenny P. Ting, John R. Tedrow, Naftali Kaminski, Woo Jin Kim, Chun Geun Lee, Yeon-Mok Oh, Jack A. Elias

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Figure 1

NLRX1 mRNA suppression in patients with COPD and its correlation with disease severity.

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NLRX1 mRNA suppression in patients with COPD and its correlation with d...
(A) NLRX1 mRNA levels in LTRC samples were plotted for controls (0, no disease) and for patients with COPD of varying severity (GOLD 1, 2, 3, and 4). (B) NLRX1 mRNA levels were compared in subjects with no disease (controls, 0) and in patients with mild-to-moderate (GOLD 1 and 2) and severe COPD (GOLD 3 and 4). (C and D) Correlation between NLRX1 mRNA levels in LTRC samples and prebronchodilator FEV1 (% of predicted value) and postbronchodilator FEV1 (% of predicted value). (E) Box-and-whisker plot for the Pittsburgh cohort depicting the relation between NLRX1 gene expression and radiologic emphysema (**P < 0.01 compared with control and the >40% emphysema group). (F and G) From the Asan cohort, NLRX1 gene transcriptome levels were plotted for controls versus patients with COPD and for controls versus patients with COPD of varying severity (GOLD 1, 2, and 3). Red bars in A, B, and G represent the mean ± SEM of the noted evaluations. Data were calculated using nonparametric Kruskal-Wallis (A), Mann-Whitney U (B), Pearson’s correlation (C and D), ANOVA (E and G), and 2-tailed t (F) tests. HU, Hounsfield units.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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