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Published on: July 10, 2018
PGC-1α regulates airway epithelial barrier dysfunction induced by house dust mite
Tsutomu Saito1, Tomohiro Ichikawa2, Tadahisa Numakura1
1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
Background:
The airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens.
Methods:
BEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated.
Results:
The amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin.
Conclusions:
The current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.
Insights
House dust mite (HDM) disrupts airway barrier function by reducing PGC-1α, a key regulator of mitochondrial biogenesis. Targeting the PAR2/TLR4/PGC-1α pathway offers a novel therapeutic strategy for asthma treatment.
Area of Science:
- Cell Biology
- Immunology
- Respiratory Medicine
Background:
- Airway epithelial barrier dysfunction is a hallmark of asthma.
- Abnormal mitochondrial biogenesis is implicated in asthma pathogenesis.
- The specific role of mitochondrial biogenesis in airway barrier defects remains unclear.
Purpose of the Study:
- To investigate the involvement of peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, in aeroallergen-induced airway barrier dysfunction.
- To elucidate the pathway through which house dust mite (HDM) affects airway barrier integrity and mitochondrial function.
Main Methods:
- BEAS-2B cells were exposed to HDM to assess PGC-1α and E-cadherin expression.
- The effects of a PGC-1α activator (SRT1720) were evaluated on HDM-induced changes.
- Transepithelial electrical resistance (TEER) was measured to assess barrier function.
- Inhibitors of PAR2, TLR4, and proteases were used to probe the underlying mechanisms.
Main Results:
- HDM exposure significantly decreased PGC-1α and E-cadherin levels in BEAS-2B cells.
- SRT1720 treatment restored PGC-1α and E-cadherin expression and ameliorated HDM-induced reduction in TEER.
- Inhibitors of PAR2, TLR4, and proteases prevented HDM-induced decreases in PGC-1α and E-cadherin.
Conclusions:
- HDM disrupts airway barrier function via a pathway involving PAR2, TLR4, and PGC-1α.
- Modulating this PAR2/TLR4/PGC-1α pathway presents a potential new therapeutic approach for asthma.
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