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NLRP3 inflammasome activation by mitochondrial ROS in bronchial epithelial cells is required for allergic
1Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University - Biomedical Research Institute of Chonbuk National University Hospital, Deokjin-gu, Jeonju, South Korea.
Abstract:
Abnormality in mitochondria has been suggested to be associated with development of allergic airway disorders. In this study, to evaluate the relationship between mitochondrial reactive oxygen species (ROS) and NLRP3 inflammasome activation in allergic asthma, we used a newly developed mitochondrial ROS inhibitor, NecroX-5. NecroX-5 reduced the increase of mitochondrial ROS generation in airway inflammatory cells, as well as bronchial epithelial cells, NLRP3 inflammasome activation, the nuclear translocation of nuclear factor-κB, increased expression of various inflammatory mediators and pathophysiological features of allergic asthma in mice. Finally, blockade of IL-1β substantially reduced airway inflammation and hyperresponsiveness in the asthmatic mice. These findings suggest that mitochondrial ROS have a critical role in the pathogenesis of allergic airway inflammation through the modulation of NLRP3 inflammasome activation, providing a novel role of airway epithelial cells expressing NLRP3 inflammasome as an immune responder.
Insights
Mitochondrial reactive oxygen species (ROS) drive allergic asthma by activating the NLRP3 inflammasome. Inhibiting mitochondrial ROS with NecroX-5 reduced asthma symptoms in mice, highlighting a new therapeutic target.
Area of Science:
- Immunology
- Mitochondrial Biology
- Respiratory Medicine
Background:
- Mitochondrial dysfunction is linked to allergic airway diseases.
- The role of mitochondrial reactive oxygen species (ROS) in asthma pathogenesis is under investigation.
Purpose of the Study:
- To investigate the relationship between mitochondrial ROS and NLRP3 inflammasome activation in allergic asthma.
- To evaluate the therapeutic potential of a novel mitochondrial ROS inhibitor, NecroX-5.
Main Methods:
- Utilized NecroX-5, a mitochondrial ROS inhibitor, in a mouse model of allergic asthma.
- Assessed mitochondrial ROS generation, NLRP3 inflammasome activation, nuclear factor-κB translocation, inflammatory mediator expression, and asthma-related pathology.
- Investigated the effect of IL-1β blockade on airway inflammation and hyperresponsiveness.
Main Results:
- NecroX-5 effectively reduced mitochondrial ROS in airway and bronchial epithelial cells.
- Inhibition of mitochondrial ROS suppressed NLRP3 inflammasome activation, NF-κB translocation, and inflammatory mediator expression.
- Treatment with NecroX-5 ameliorated the pathophysiological features of allergic asthma in mice.
- Blocking IL-1β significantly decreased airway inflammation and hyperresponsiveness.
Conclusions:
- Mitochondrial ROS play a crucial role in allergic airway inflammation via NLRP3 inflammasome activation.
- Airway epithelial cells expressing NLRP3 inflammasome act as immune responders in asthma.
- Targeting mitochondrial ROS presents a potential therapeutic strategy for allergic asthma.
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