Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation.,Cell Host & Microbe

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Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation.
Cell Host & Microbe ( IF 30.3 ) Pub Date : 2020-02-27 , DOI: 10.1016/j.chom.2020.02.006
Darin L Wiesner ₁ , Richard M Merkhofer ₁ , Carole Ober ₂ , Gregory C Kujoth ₁ , Mengyao Niu ₃ , Nancy P Keller ₄ , James E Gern ₅ , Rebecca A Brockman-Schneider ₁ , Michael D Evans ₆ , Daniel J Jackson ₅ , Thomas Warner ₇ , Nizar N Jarjour ₈ , Stephane J Esnault ₈ , Michael B Feldman ₉ , Matthew Freeman ₁₀ , Hongmei Mou ₁₁ , Jatin M Vyas ₁₂ , Bruce S Klein ₁₃

Affiliation

Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
Department of Medical Microbiology and Immunology University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Medical Microbiology and Immunology University of Wisconsin-Madison, Madison, WI 53706, USA; School of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Boston, MA 02115, USA.
School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
The Mucosal Immunology & Biology Research Center, Harvard Medical School, Boston, MA 02115, USA; Division of Pediatric Pulmonary Medicine, Harvard Medical School, Boston, MA 02115, USA.
Division of Infectious Disease, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medical Microbiology and Immunology University of Wisconsin-Madison, Madison, WI 53706, USA.

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.

中文翻译：

Club Cell TRPV4 用作驱动肺部过敏性炎症的损伤传感器。

气道上皮是第一个接触吸入刺激物并报告危险的体表。在这里，我们报告了上皮细胞如何识别和响应曲霉属的气敏性过敏原碱性蛋白酶 1 (Alp1)，因为蛋白酶是引起哮喘的许多过敏原的关键成分。在小鼠模型中，Alp1 引发辅助 T (Th) 细胞依赖性肺嗜酸性粒细胞增多，这是由细支气管俱乐部细胞对 Alp1 的快速反应引发的。Alp1 会破坏细支气管细胞连接，从而触发通过细支气管俱乐部细胞内的钙调神经磷酸酶发出的钙流信号，从而引发炎症。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/蛋白质表达联系起来。TRPV4 也是俱乐部细胞使小鼠对 Alp1 敏感的必要和充分条件。因此，

更新日期：2020-04-20

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