2. Academic Validation
  3. Epithelial cell membrane perforation induces allergic airway inflammation

Epithelial cell membrane perforation induces allergic airway inflammation

  • Nature. 2025 Sep;645(8080):475-483. doi: 10.1038/s41586-025-09331-1.
Kejian Shi # 1 2,  Yao Lv # 2 3,  Chunqiu Zhao # 4 5,  Huan Zeng 2,  Yeqiong Wang 2,  Yuxuan Liu 2,  Lin Li 2,  She Chen 2 6,  Pu Gao 7 8,  Feng Shao 2 6,  Mo Xu 9 10
Affiliations

Affiliations

  • 1 School of Life Sciences, Beijing Normal University, Beijing, China.
  • 2 National Institute of Biological Sciences, Beijing, Beijing, China.
  • 3 Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, School of Life Sciences, Tsinghua University, Beijing, China.
  • 4 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 5 University of Chinese Academy of Sciences, Beijing, China.
  • 6 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
  • 7 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. gaopu@ibp.ac.cn.
  • 8 University of Chinese Academy of Sciences, Beijing, China. gaopu@ibp.ac.cn.
  • 9 National Institute of Biological Sciences, Beijing, Beijing, China. xumo@nibs.ac.cn.
  • 10 Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. xumo@nibs.ac.cn.
  • # Contributed equally.
PMID: 40739348 DOI: 10.1038/s41586-025-09331-1
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.

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