Epithelial damage triggers allergic inflammation

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Science Signaling  17 Mar 2020:
Vol. 13, Issue 623, eabb6894
DOI: 10.1126/scisignal.abb6894

A fungal protease induces allergic inflammation by damaging the lung epithelium.

Inhaled allergens derived from molds can trigger asthma. Alp1, an alkaline protease secreted by Aspergillus species to acquire nutrients from the environment, is associated with severe asthma and has been proposed to stimulate type 2 immune responses by damaging the lung epithelium. Wiesner et al. found that inhaled, active Aspergillus fumigatus Asp1 in mice induced bronchial infiltration of immune cells and morphological changes in airway epithelia that are typical of allergic asthma. Ablation of a subset of bronchiolar epithelial cells called club cells reduced these pathologies. Asp1 induced the recruitment of dendritic cells (DCs) into the airway epithelia in a manner dependent on the C-C motif chemokine ligand 2 (CCL2), a chemoattractant that is released by damaged epithelial cells. Preventing DC recruitment to the lung reduced the accumulation of T helper cells, which drive allergic inflammation. In both mice and primary human cells, Alp1 damaged the junctions between lung epithelial cells. In mice, junction damage elicited by the cationic peptide poly -arginine promoted an increase in the number of T cells in the lungs. Alp1-induced immune cell recruitment required both the mechanosensitive cation channel transient receptor potential vanilloid 4 (TRPV4) and the calcium-dependent phosphatase calcineurin in club cells. The authors identified a single-nucleotide polymorphism in human TRPV4 that is associated with increased TRPV4 expression and sensitization to fungal allergens and asthma. These findings define a model that may play a role in fungus-induced allergic asthma, in which fungal proteases damage the lung epithelium, leading to the recruitment of immune cells that drive allergic inflammation.

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