Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
Cell Host Microbe. 2020 Apr 8;27(4):614-628.e6. doi: 10.1016/j.chom.2020.02.006. Epub 2020 Mar 3.
Airway epithelium is the first body surface to contact inhaled irritants and report danger. Here, we report how epithelial cells recognize and respond to aeroallergen alkaline protease 1 (Alp1) of Aspergillus sp., because proteases are critical components of many allergens that provoke asthma. In a murine model, Alp1 elicits helper T (Th) cell-dependent lung eosinophilia that is initiated by the rapid response of bronchiolar club cells to Alp1. Alp1 damages bronchiolar cell junctions, which triggers a calcium flux signaled through calcineurin within club cells of the bronchioles, inciting inflammation. In two human cohorts, we link fungal sensitization and/or asthma with SNP/protein expression of the mechanosensitive calcium channel, TRPV4. TRPV4 is also necessary and sufficient for club cells to sensitize mice to Alp1. Thus, club cells detect junction damage as mechanical stress, which signals danger via TRPV4, calcium, and calcineurin to initiate allergic sensitization.
气道上皮细胞是第一个接触吸入性刺激物并报告危险的身体表面。在这里，我们报告上皮细胞如何识别和响应曲霉属的气传过敏原碱性蛋白酶 1（Alp1），因为蛋白酶是许多引发哮喘的过敏原的关键成分。在小鼠模型中，Alp1 引发依赖辅助性 T（Th）细胞的肺嗜酸性粒细胞增多症，这是由细支气管 club 细胞对 Alp1 的快速反应引发的。Alp1 破坏细支气管细胞连接，这触发了通过细支气管 club 细胞内钙调神经磷酸酶的钙流信号，引发炎症。在两个人类队列中，我们将真菌致敏和/或哮喘与机械敏感性钙通道 TRPV4 的 SNP/蛋白表达联系起来。TRPV4 也是 club 细胞使小鼠对 Alp1 敏感所必需和充分的。因此，club 细胞将细胞连接损伤检测为机械应激，通过 TRPV4、钙和钙调神经磷酸酶发出危险信号，启动过敏致敏。
