PGC-1[alpha] regulates airway epithelial barrier dysfunction induced by house dust mite

• Published in: Respiratory research 2021-02, Vol.22 (1)
• Main Authors: Saito, Tsutomu, Ichikawa, Tomohiro, Numakura, Tadahisa, Yamada, Mitsuhiro, Koarai, Akira, Fujino, Naoya, Murakami, Koji, Yamanaka, Shun, Sasaki, Yusaku, Kyogoku, Yorihiko, Itakura, Koji, Sano, Hirohito, Takita, Katsuya, Tanaka, Rie, Tamada, Tsutomu, Ichinose, Masakazu, Sugiura, Hisatoshi
• Format: Article
• Language: English
• Subjects: Asthma; Development and progression; Epithelium; Genetic aspects; Health aspects; Mitochondrial biogenesis; Transcription factors
• ISSN: 1465-9921
• DOI: 10.1186/s12931-021-01663-6

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 [gamma] coactivator-1alpha (PGC-1[alpha]), 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-1[alpha] and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1[alpha] 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-1[alpha] and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1[alpha] 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 PGC1[alpha] and E-cadherin. Conclusions The current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1[alpha]-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma. Keywords: Asthma, Airway barrier dysfunction, PGC-1[alpha], House dust mite