Epithelial cell membrane perforation induces allergic airway inflammation

• 成果类型: Article
• 署名作者: Shi, Kejian; Lv, Yao; Zhao, Chunqiu; Zeng, Huan; Wang, Yeqiong; Liu, Yuxuan; Li, Lin; Chen, She; Gao, Pu; Shao, Feng; Xu, Mo
• 署名单位: Beijing Normal University; National Institute of Biological Sciences, Beijing; Tsinghua University; Chinese Academy of Sciences; Institute of Biophysics, CAS; Nanjing Institute of Geology & Paleontology, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Tsinghua University
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09331-1
• 发表日期: 2025-09-01
• 页码: 475-+
• 关键词: pore-forming proteins; lung inflammation; receptor; expression; chemokine; toxin; Visualization; activation; cytolysin; cloning

摘要

Allergens that induce allergic airway inflammation are highly diverse, but they commonly activate type 2 immune responses(1,2). Airway epithelial cells are crucial in allergen sensing(3-5). However, the shared features among diverse allergens that elicit similar innate responses, and their epithelial detection mechanisms, remain poorly defined(1,2,6-9). 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.