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Epithelial cell membrane perforation induces allergic airway inflammation

Published:30 July 2025 DOI: 10.1038/s41586-025-09331-1
Kejian Shi, Yao Lv, Chunqiu Zhao, Huan Zeng, Yeqiong Wang, Yuxuan Liu, Lin Li, She Chen, Pu Gao, Feng Shao, Mo Xu

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. The ability to form pores in the plasma membrane of host airway epithelial cells is a common feature of many structurally diverse allergens that induce type 2 immune responses by stimulating IL-33 release and causing Ca2+ influx.

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Procduct Name CAS Molecular Formula Supplier Price
Trametinib 871700-17-3 C26H23FIN5O4 381 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 381 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 381 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 381 suppliers $28.00-$4391.10
BAPTA-AM 126150-97-8 C34H40N2O18 233 suppliers $13.00-$1530.00
BAPTA-AM 126150-97-8 C34H40N2O18 233 suppliers $13.00-$1530.00
BAPTA-AM 126150-97-8 C34H40N2O18 233 suppliers $13.00-$1530.00
BAPTA-AM 126150-97-8 C34H40N2O18 233 suppliers $13.00-$1530.00
Trametinib 871700-17-3 - Inquiry
Trametinib 871700-17-3 - Inquiry

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