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Published on: June 14, 2016
Oxidative stress induces MUC5AC expression through mitochondrial damage-dependent STING signaling in human bronchial
Yutaka Nishida1, Hisako Yagi1, Masaya Ota1,2
1Department of Pediatrics Gunma University Graduate School of Medicine Gunma Japan.
Abstract:
Oxidative stress increases the production of the predominant mucin MUC5AC in airway epithelial cells and is implicated in the pathogenesis of bronchial asthma and chronic obstructive pulmonary disease. Oxidative stress impairs mitochondria, releasing mitochondrial DNA into the cytoplasm and inducing inflammation through the intracytoplasmic DNA sensor STING (stimulator of interferon genes). However, the role of innate immunity in mucin production remains unknown. We aimed to elucidate the role of innate immunity in mucin production in airway epithelial cells under oxidative stress. Human airway epithelial cell line (NCI-H292) and normal human bronchial epithelial cells were used to confirm MUC5AC expression levels by real-time PCR when stimulated with hydrogen peroxide (H2O2). MUC5AC transcriptional activity was increased and mitochondrial DNA was released into the cytosol by H2O2. Mitochondrial antioxidants were used to confirm the effects of mitochondrial oxidative stress where antioxidants inhibited the increase in MUC5AC transcriptional activity. Cyclic GMP-AMP synthase (cGAS) or STING knockout (KO) cells were generated to investigate their involvement. H2O2-induced MUC5AC expression was suppressed in STING KO cells, but not in cGAS KO cells. The epidermal growth factor receptor was comparably expressed in STING KO and wild-type cells. Thus, mitochondria and STING play important roles in mucin production in response to oxidative stress in airway epithelial cells.
Insights
Oxidative stress boosts mucin MUC5AC production in airway cells via mitochondrial damage and STING signaling. This innate immune pathway is crucial for mucin overproduction in respiratory diseases.
Area of Science:
- Cell Biology
- Immunology
- Respiratory Medicine
Background:
- Oxidative stress elevates MUC5AC mucin production in airway epithelial cells, contributing to asthma and COPD pathogenesis.
- Mitochondrial dysfunction under oxidative stress releases DNA, activating the STING-mediated inflammatory pathway.
Purpose of the Study:
- To investigate the role of innate immunity, specifically the STING pathway, in regulating mucin production in airway epithelial cells during oxidative stress.
Main Methods:
- Utilized human airway epithelial cell lines (NCI-H292, normal bronchial epithelial cells) stimulated with hydrogen peroxide (H₂O₂).
- Assessed MUC5AC expression via real-time PCR and evaluated mitochondrial DNA release.
- Employed mitochondrial antioxidants and generated STING/cGAS knockout cell lines to determine pathway involvement.
Main Results:
- H₂O₂ increased MUC5AC transcription and induced mitochondrial DNA release.
- Mitochondrial antioxidants attenuated the H₂O₂-induced rise in MUC5AC expression.
- STING knockout cells showed suppressed H₂O₂-induced MUC5AC expression, while cGAS knockout cells did not.
Conclusions:
- Mitochondria and the STING pathway are critical regulators of mucin production in airway epithelial cells responding to oxidative stress.
- This highlights a novel innate immune mechanism contributing to mucin overproduction in respiratory diseases.
