清华大学徐墨团队的最新研究探明了上皮细胞膜穿孔可诱发过敏性气道炎症。这一研究成果发表在2025年7月30日出版的国际学术期刊《自然》上。

在这里，研究人员确定孔隙形成蛋白是过敏性气道炎症的常见刺激物之一，并揭示其免疫激活机制。以流行的霉菌过敏原交替孢霉为模型，建立了2型先天免疫感知的体外系统。六步生化分离鉴定出Aeg-S和Aeg-L是核心的免疫刺激成分。生化重构和低温电镜显示这些蛋白形成16-20粒的跨膜孔复合物。它们的协同穿孔作为真正的2型免疫佐剂，支持抗原特异性T辅助2和免疫球蛋白E反应。缺乏孔形成活性的基因工程菌株在小鼠中不会引起过敏反应。

此外，不同物种的成孔蛋白，尽管结构和膜靶不同，但足以引发呼吸道过敏。气道上皮细胞穿孔通过两种机制启动过敏反应：一种触发IL-33释放，另一种涉及Ca²⁺内流，其激活MAPK信号传导和2型炎症基因表达。这些发现为了解2型免疫反应如何检测由结构多样化刺激引起的常见扰动提供了见解。靶向上皮穿孔的下游信号可能为治疗呼吸道过敏开辟新的途径。

研究人员表示，诱发过敏性气道炎症的过敏原多种多样，但它们通常会激活2型免疫反应。气道上皮细胞在过敏原感知中起着至关重要的作用。然而，引起相似先天反应的不同过敏原之间的共同特征及其上皮检测机制仍然不明确。

附：英文原文

Title: Epithelial cell membrane perforation induces allergic airway inflammation

Author: Shi, Kejian, Lv, Yao, Zhao, Chunqiu, Zeng, Huan, Wang, Yeqiong, Liu, Yuxuan, Li, Lin, Chen, She, Gao, Pu, Shao, Feng, Xu, Mo

Issue&Volume: 2025-07-30

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 sensing3,4,5. However, the shared features among diverse allergens that elicit similar innate responses, and their epithelial detection mechanisms, remain poorly defined1,2,6,7,8,9. 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.

DOI: 10.1038/s41586-025-09331-1

Source: https://www.nature.com/articles/s41586-025-09331-1