Force sensors – TRPV4 and Piezo1 – calibrate allergic response to aspergillus protease allergen by airway epithelial cells 3757

Description Asthma affects over 10% of U.S. residents and is the fastest-growing chronic illness in children, with nearly half of asthmatics sensitized to fungal proteases, such as Aspergillus protease (Asp f 13). Our research suggests that club cells in the bronchiolar airways trigger allergic sensitization when Asp f 13 disrupts cellular junctions, though the biochemical signaling mechanisms remain unclear. Airway barrier integrity relies on epithelial cell junctions, which maintain cell shape through a balance of intercellular and cytoskeletal forces. Protease-induced junction disruption may disturb this balance, potentially activating mechanotransduction pathways in club cells to detect damage and initiate allergic responses. Using in vivo and in vitro models, we studied mechanosensors TRPV4 and Piezo1 in club cells. TRPV4 promoted allergic sensitization, while Piezo1 had an opposing role. Deleting Piezo1 exacerbated allergic responses to Asp f 13, whereas Piezo1 agonists reduced the response in wild-type but not Piezo1-deficient mice. In lung epithelial cells, Asp f 13 reduced nuclear YAP1, further destabilized by TRPV4 activation. Meanwhile, nuclear CREB levels decreased with protease exposure but were stabilized by Piezo1 agonists. These findings suggest TRPV4 and Piezo1 modulate mechanical signaling pathways in epithelial cells, balancing the allergic and wound-healing responses to protease-induced injury.