Therapeutic potential of a Bax inhibitor-1/TMBIM6 antagonist (BIA) and its analogues in Aspergillus fumigatus-induced asthma via dual targeting of AKT and epithelial-derived inflammatory cytokines.

内容摘要

Aspergillus fumigatus (A. fumigatus) exposure causes of severe allergic asthma, characterized by airway inflammation and epithelial dysfunction. TMBIM6 (Bax inhibitor-1) has been implicated in airway epithelial stress responses and AKT signalling. This study aimed to elucidate the therapeutic potential of the drug called the Bax inhibitor-1 antagonist (BIA) and its structural analogues in a murine model of A. fumigatus-induced allergic asthma. 19 BIA analogues were synthesized and evaluated alongside the original drug BIA in a murine model of A. fumigatus-induced airway inflammation. Inflammatory phenotypes were assessed by analysing bronchoalveolar lavage fluid (BALF), lung histopathology, quantification of T-helper 2 (Th2) and Th17 cytokines. Mechanistic investigations evaluated the AKT/NLRP3 pathway and epithelial-derived cytokines, while TMBIM6-mediated ER Ca2+ flux was monitored using a TMBIM6-GCaMP3 reporter system. BIA and its analogues significantly attenuated inflammatory cell infiltration, goblet cell hyperplasia, airway remodelling and Th2-associated cytokine expression in the lungs of A. fumigatus-challenged mice. BIA and selected analogues also suppressed Th17-associated cytokine expression. Moreover, BIA analogues preferentially reduced epithelial-derived cytokine expression. Mechanistically, BIA and select analogues markedly suppressed AKT phosphorylation and NLRP3 expression in lungs and airway epithelial cells. Pharmacological inhibition and TMBIM6 knockdown supported the involvement of the TMBIM6/AKT/NLRP3 signalling axis, while BIA and select analogues inhibited TMBIM6-mediated ER calcium leakage. BIA and its analogues attenuate A. fumigatus-induced allergic lung inflammation by targeting the TMBIM6/calcium/AKT axis, suppressing NLRP3 signalling and epithelial-derived inflammatory cytokines. These findings highlight this axis as a promising therapeutic target for fungal-associated airway inflammation.