Epithelial cell membrane perforation induces allergic airway inflammation

Kejian Shi, Yao Lv, Chunqiu Zhao, Huan Zeng, Yeqiong Wang, Yuxuan Liu, Lin Li, She Chen, Pu Gao (), Feng Shao and Mo Xu ()
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Kejian Shi: Beijing Normal University
Yao Lv: Beijing
Chunqiu Zhao: Chinese Academy of Sciences
Huan Zeng: Beijing
Yeqiong Wang: Beijing
Yuxuan Liu: Beijing
Lin Li: Beijing
She Chen: Beijing
Pu Gao: Chinese Academy of Sciences
Feng Shao: Beijing
Mo Xu: Beijing

Nature, 2025, vol. 645, issue 8080, 475-483

Abstract: Abstract Allergens that induce allergic airway inflammation are highly diverse, but they commonly activate type 2 immune responses1,2. Airway epithelial cells are crucial in allergen sensing3–5. However, the shared features among diverse allergens that elicit similar innate responses, and their epithelial detection mechanisms, remain poorly defined1,2,6–9. Here we identify pore-forming proteins as one of the common stimuli of allergic airway inflammation and reveal their immune-activation mechanisms. Using the prevalent mould allergen Alternaria alternata as a model, we established an in vitro system to investigate type 2 innate immune sensing. A six-step biochemical fractionation identified Aeg-S and Aeg-L as the core immune-stimulatory components. Biochemical reconstitution and cryo-electron microscopy reveal that these proteins form 16- to 20-mer transmembrane pore complexes. Their cooperative perforation acts as a bona fide type 2 immune adjuvant to support antigen-specific T helper 2 and immunoglobulin E responses. Genetically engineered A. alternata strains that lack pore-forming activity do not induce allergic responses in mice. Furthermore, pore-forming proteins from various species, despite structural and membrane target differences, are sufficient to trigger respiratory allergies. Perforations in airway epithelial cells initiate allergic responses through two mechanisms: one triggers IL-33 release, and the other involves Ca2+ influx, which activates MAPK signalling and type 2 inflammatory gene expression. These findings provide insight into how type 2 immune responses detect common perturbations caused by structurally diverse stimuli. Targeting downstream signalling of epithelial perforation may open new avenues for treating respiratory allergies.

Date: 2025
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DOI: 10.1038/s41586-025-09331-1

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