Targeting PGAM5 attenuates airway inflammation in asthma by inhibiting HMGB1 release in bronchial epithelium

Previous studies have demonstrated that high-mobility group box protein 1(HMGB1) was increased and released to the extracellular and participated in the pathogenesis of steroid-insensitive asthma induced by toluene diisocyanate (TDI). Mitochondrial dysfunction of bronchial epithelia is a critical feature in TDI asthma. However, whether mitochondrial dysfunction regulated HMGB1 release in asthma remains unknown. The aim of this study was to explore whether phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein, can regulate HMGB1 release in TDI-induced asthma. The gene expression data series (GSE) 67472 from gene expression omnibus (GEO) database was analyzed to compare the levels of PGAM5 in airway epithelial cells from asthma patients and healthy individuals. Male C57BL/6J mice were sensitized and challenged with TDI and treated with the PGAM5 inhibitor LFHP-1c. In vitro, human bronchial epithelial cells(16HBE) were stimulated by TDI-human serum albumin (HSA) and pretreated with PGAM5 siRNA. In this study, we observed PGAM5 expression was notably increased in airway epithelial cells of asthma patients and TDI-induced asthma mice. In vivo, inhibition of PGAM5 significantly ameliorated airway inflammation, airway hyperresponsiveness (AHR) and mucus hypersecretion, coupled with the decrease of pulmonary HMGB1 expression and release in TDI-exposed mice. In vitro, inhibition of PGAM5 improved mitochondrial dysfunction, decreased the production of reactive oxygen species (ROS) in mitochondrial. Knockdown of PGAM5 reduced the release of cytochrome C (cyt c) and HMGB1 release in TDI-induced asthma. Mechanistically, PGAM5 in bronchial epithelial cells treated by TDI-HSA significantly increased the dephosphorylation of Bax at the S184 residue, promoted the translocation of Bax to mitochondria, and contributed to the activation of mitochondrial-dependent apoptosis in TDI-induced asthma. Based on these findings, we uncovered a novel regulatory mechanism by which high PGAM5 expression promotes airway inflammation by mediating HMGB1 release in TDI-induced asthma, identifying the therapeutic effects of targeting PGAM5 in steroid-insensitive asthma model.