Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation

Abstract

Highlights d An inhaled fungal protease allergen damages the junctions of bronchiolar club cells d The mechanosensor TRPV4 senses the junction injury, triggering allergic inflammation d TRPV4 is sufficient for inflammation in mice and linked with fungal asthma in humans d Calcineurin mediates TRPV4-dependent calcium signaling within bronchiolar club cells

Aspergillus fumigatus Protease Alkaline Protease 1 (Alp1): A New Therapeutic Target for Fungal Asthma

“…Beyond this cascade, Alp1 also enhances intracellular Ca 2+ mobilization in response to contractile agonists [18], although the mechanisms underlying this phenotype are less clear. For example, Alp1-induced Ca 2+ mobilization in ASM cells could involve TRPV4, as was recently reported to be the case for bronchiolar club cells [20], but this remains to be ascertained.…”

“…The mechanism(s) underlying Alp1 deposition in the bronchial submucosa in asthma remain unclear. In a recent study, co-administration of Alp1 and biotin to the airways of naïve mice elicited widespread disruption of airway epithelial integrity, as evidenced by the presence of biotin in lung tissue [20]. Alp1 also reduced the transepithelial resistance (TER) of epithelial cell monolayers in vitro and degraded the adherens junction protein E-cadherin, indicating increased para-cellular permeability.…”

“…Alp1 is a member of the subtilisin/peptidase S8 family of serine proteases, which can be found in bacteria, fungi, and archaea species [19]. These proteases contain a characteristic Asp/His/Ser catalytic triad but are not substrate-specific [20]. The active site is formed by tertiary conformation of the protease, where the Ser residue initiates a nucleophilic attack on the carbonyl carbon atom of the substrate.…”

“…Wiesner et al proposed that the voltage-gated Ca 2+ channel TRPV4 is a mechanosensor of Alp1-induced junctional damage in epithelial cells. Activation of TRPV4 by Alp1 elicits a Ca 2+ -calcineurin-mediated allergic inflammatory cascade initiated by bronchiolar club cells (specialized cells within the ciliated epithelium) and recruitment of monocyte-derived dendritic cells (DCs) and T helper type 2 (Th2) cells [20]. Club-cell-specific Trpv4 deletion in mice resulted in significantly decreased, but not absent, DC, eosinophil and Th2 recruitment to the lungs.…”

“…PAR2 is also known to be activated by allergen proteases including Der p 9 and Der p 3 [23] from house dust mites, as well as the alkaline serine protease (AASP) of the mold Alternaria alternata, and Pen c 13 from the fungus P. citrinum [24][25][26]. In contrast, PAR2 peptides are not cleaved by Alp1 [20]. Furthermore, PAR2 inhibition does not affect Alp1-induced mediator (PGE2) secretion by human bronchial epithelial cells [27].…”