BackgroundSevere refractory, neutrophilic asthma remains an unsolved clinical problem. STING agonists induce a neutrophilic response in the airways, suggesting that STING activation may contribute to the triggering of neutrophilic exacerbations. We aim to determine whether STING‐induced neutrophilic lung inflammation mimics severe asthma.MethodsWe developed new models of neutrophilic lung inflammation induced by house dust mite (HDM) plus STING agonists diamidobenzimidazole (diABZI) or cGAMP in wild‐type, and conditional‐STING‐deficient mice. We measured DNA damage, cell death, NETs, cGAS/STING pathway activation by immunoblots, N1/N2 balance by flow cytometry, lung function by plethysmography, and Th1/Th2 cytokines by multiplex. We evaluated diABZI effects on human airway epithelial cells from healthy or patients with asthma, and validated the results by transcriptomic analyses of rhinovirus infected healthy controls vs patients with asthma.ResultsDiABZI administration during HDM challenge increased airway hyperresponsiveness, neutrophil recruitment with prominent NOS2+ARG1− type 1 neutrophils, protein extravasation, cell death by PANoptosis, NETs formation, extracellular dsDNA release, DNA sensors activation, IFNγ, IL‐6 and CXCL10 release. Functionally, STING agonists exacerbated airway hyperresponsiveness. DiABZI caused DNA and epithelial barrier damage, STING pathway activation in human airway epithelial cells exposed to HDM, in line with DNA‐sensing and PANoptosis pathways upregulation and tight‐junction downregulation induced by rhinovirus challenge in patients with asthma.ConclusionsOur study identifies that triggering STING in the context of asthma induces cell death by PANoptosis, fueling the flame of inflammation through a mixed Th1/Th2 immune response recapitulating the features of severe asthma with a prognostic signature of type 1 neutrophils.

中文翻译：

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响应屋尘螨的中性粒细胞哮喘发作的 STING 依赖性诱导


背景重度难治性中性粒细胞性哮喘仍然是一个未解决的临床问题。STING 激动剂在气道中诱导中性粒细胞反应，表明 STING 激活可能有助于触发中性粒细胞恶化。我们的目标是确定 STING 诱导的中性粒细胞性肺炎症是否类似于严重的哮喘。方法我们开发了屋尘螨 （HDM） 加 STING 激动剂二胺苯并咪唑 （diABZI） 或 cGAMP 在野生型和条件性 STING 缺陷小鼠中诱导的中性粒细胞性肺炎症的新模型。我们测量了 DNA 损伤、细胞死亡、NETs、免疫印迹的 cGAS/STING 通路激活、流式细胞术的 N1/N2 平衡、体积描记法的肺功能以及多重检测的 Th1/Th2 细胞因子。我们评估了 diABZI 对健康或哮喘患者人气道上皮细胞的影响，并通过鼻病毒感染的健康对照与哮喘患者的转录组学分析验证了结果。结果HDM 攻击期间的 DiABZI 给药增加了气道高反应性、中性粒细胞募集伴有突出的 NOS2+ARG1− 1 型中性粒细胞、蛋白质外渗、PANoptosis导致的细胞死亡、NETs 形成、细胞外 dsDNA 释放、DNA 传感器激活、IFNγ、IL-6 和 CXCL10 释放。在功能上，STING 激动剂加剧了气道高反应性。DiABZI 导致 DNA 和上皮屏障损伤，暴露于 HDM 的人气道上皮细胞中的 STING 通路激活，与哮喘患者鼻病毒攻击诱导的 DNA 感应和 PANoptosis 通路上调和紧密连接下调一致。结论我们的研究发现，在哮喘的情况下触发 STING 会诱导 PANoptosis的细胞死亡，通过混合的 Th1/Th2 免疫反应助长炎症的火焰，概括了严重哮喘的特征，具有 1 型中性粒细胞的预后特征。