Key Points Airway epithelial cGAS plays a key role in asthma pathogenesis. cGAS may be a promising target against allergic airway inflammation. DNA damage could lead to the accumulation of cytosolic DNA, and the cytosolic DNA–sensing pathway has been implicated in multiple inflammatory diseases. However, the role of cytosolic DNA–sensing pathway in asthma pathogenesis is still unclear. This article explored the role of airway epithelial cyclic GMP-AMP synthase (cGAS), the major sensor of cytosolic dsDNA, in asthma pathogenesis. Cytosolic dsDNA accumulation in airway epithelial cells (ECs) was detected in the setting of allergic inflammation both in vitro and in vivo. Mice with cGAS deletion in airway ECs were used for OVA- or house dust mite (HDM)–induced allergic airway inflammation. Additionally, the effects of cGAS knockdown on IL-33–induced GM-CSF production and the mechanisms by which IL-33 induced cytosolic dsDNA accumulation in human bronchial epithelial (HBE) cells were explored. Increased accumulation of cytosolic dsDNA was observed in airway epithelium of OVA- or HDM-challenged mice and in HBE cells treated with IL-33. Deletion of cGAS in the airway ECs of mice significantly attenuated the allergic airway inflammation induced by OVA or HDM. Mechanistically, cGAS participates in promoting TH2 immunity likely via regulating the production of airway epithelial GM-CSF. Furthermore, Mito-TEMPO could reduce IL-33–induced cytoplasmic dsDNA accumulation in HBE cells possibly through suppressing the release of mitochondrial DNA into the cytosol. In conclusion, airway epithelial cGAS plays an important role via sensing the cytosolic dsDNA in asthma pathogenesis and could serve as a promising therapeutic target against allergic airway inflammation.

中文翻译：

---

气道上皮 cGAS 是诱导实验性过敏性气道炎症的关键

要点 气道上皮 cGAS 在哮喘发病机制中起关键作用。cGAS 可能是对抗过敏性气道炎症的有希望的靶点。DNA 损伤可能导致细胞质 DNA 的积累，细胞质 DNA 传感途径与多种炎症疾病有关。然而，胞质 DNA 传感途径在哮喘发病机制中的作用仍不清楚。本文探讨了气道上皮环 GMP-AMP 合酶 (cGAS)（胞质 dsDNA 的主要传感器）在哮喘发病机制中的作用。在体外和体内过敏性炎症的情况下，都检测到气道上皮细胞 (ECs) 中的胞质 dsDNA 积累。气道内皮细胞 cGAS 缺失的小鼠用于治疗 OVA 或屋尘螨 (HDM) 引起的过敏性气道炎症。此外，探讨了 cGAS 敲低对 IL-33 诱导的 GM-CSF 产生的影响以及 IL-33 诱导人支气管上皮 (HBE) 细胞中胞质 dsDNA 积累的机制。在 OVA 或 HDM 攻击的小鼠的气道上皮和用 IL-33 处理的 HBE 细胞中观察到胞质 dsDNA 的积累增加。小鼠气道ECs中cGAS的缺失显着减轻了OVA或HDM诱导的过敏性气道炎症。从机制上讲，cGAS 可能通过调节气道上皮 GM-CSF 的产生参与促进 TH2 免疫。此外，Mito-TEMPO 可能通过抑制线粒体 DNA 释放到细胞质中来减少 HBE 细胞中 IL-33 诱导的细胞质 dsDNA 积累。综上所述，