STING 依赖性诱导HDM诱导的中性粒细胞性哮喘加重
2024/11/29
摘要
背景：严重的难治性中性粒细胞性哮喘仍是一个尚未解决的临床问题。STING激动剂会诱发气道中性粒细胞反应，这表明STING激活可能有助于引发中性粒细胞性哮喘加重。我们旨在确定STING诱导的中性粒细胞肺部炎症是否会模拟重症哮喘。
方法：我们在野生型小鼠和条件性STING缺陷小鼠体内建立了由屋尘螨（HDM）和STING激动剂二氨基苯并咪唑（diABZI）或cGAMP诱导的中性粒细胞肺部炎症新模型。我们通过免疫印迹法测量了 DNA损伤、细胞死亡、NET、cGAS/STING通路激活，通过流式细胞术测量了N1/N2平衡，通过体积描记法测量了肺功能，并通过多重方法测量了Th1/Th2细胞因子。我们评估了二氮苯对健康人或哮喘患者气道上皮细胞的影响，并通过鼻病毒感染健康对照组与哮喘患者的转录组分析验证了结果。
结果：在HDM诱导时服用DiABZI会增加气道高反应性、中性粒细胞募集（NOS2+ARG1-1型中性粒细胞显著）、蛋白质外渗、细胞凋亡、NETs形成、细胞外dsDNA释放、DNA感受器激活、IFNγ、IL-6和CXCL10释放。在功能上，STING激动剂会加剧气道高反应性。DiABZI会导致暴露于HDM的人气道上皮细胞DNA和上皮屏障损伤、STING通路活化，这与哮喘患者鼻病毒挑战诱导的DNA传感和PANoptosis通路上调和紧密连接下调是一致的。
结论：我们的研究发现，在哮喘的情况下触发STING会诱导细胞通过PAN细胞凋亡而死亡，并通过 Th1/Th2混合免疫反应助长炎症，这种反应再现了严重哮喘的特征，并具有1型中性粒细胞的预后特征。
STING-dependent induction of neutrophilic asthma exacerbation in response to house dust mite
Y. Messaoud-Nacer, E. Culerier, S. Rose, I. Maillet, R. Boussad, C. Veront, et al.
Abstract
BACKGROUND:Severe 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.
METHODS:We 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.
RESULTS:DiABZI 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, IFN gamma, 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.
CONCLUSIONS: Our 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.
背景：严重的难治性中性粒细胞性哮喘仍是一个尚未解决的临床问题。STING激动剂会诱发气道中性粒细胞反应，这表明STING激活可能有助于引发中性粒细胞性哮喘加重。我们旨在确定STING诱导的中性粒细胞肺部炎症是否会模拟重症哮喘。
方法：我们在野生型小鼠和条件性STING缺陷小鼠体内建立了由屋尘螨（HDM）和STING激动剂二氨基苯并咪唑（diABZI）或cGAMP诱导的中性粒细胞肺部炎症新模型。我们通过免疫印迹法测量了 DNA损伤、细胞死亡、NET、cGAS/STING通路激活，通过流式细胞术测量了N1/N2平衡，通过体积描记法测量了肺功能，并通过多重方法测量了Th1/Th2细胞因子。我们评估了二氮苯对健康人或哮喘患者气道上皮细胞的影响，并通过鼻病毒感染健康对照组与哮喘患者的转录组分析验证了结果。
结果：在HDM诱导时服用DiABZI会增加气道高反应性、中性粒细胞募集（NOS2+ARG1-1型中性粒细胞显著）、蛋白质外渗、细胞凋亡、NETs形成、细胞外dsDNA释放、DNA感受器激活、IFNγ、IL-6和CXCL10释放。在功能上，STING激动剂会加剧气道高反应性。DiABZI会导致暴露于HDM的人气道上皮细胞DNA和上皮屏障损伤、STING通路活化，这与哮喘患者鼻病毒挑战诱导的DNA传感和PANoptosis通路上调和紧密连接下调是一致的。
结论：我们的研究发现，在哮喘的情况下触发STING会诱导细胞通过PAN细胞凋亡而死亡，并通过 Th1/Th2混合免疫反应助长炎症，这种反应再现了严重哮喘的特征，并具有1型中性粒细胞的预后特征。
（中日友好医院呼吸与危重症医学科 李春晓 摘译 林江涛 审校）
（Allergy 2024 DOI: 10.1111/all.16369）
（Allergy 2024 DOI: 10.1111/all.16369）
STING-dependent induction of neutrophilic asthma exacerbation in response to house dust mite
Y. Messaoud-Nacer, E. Culerier, S. Rose, I. Maillet, R. Boussad, C. Veront, et al.
Abstract
BACKGROUND:Severe 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.
METHODS:We 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.
RESULTS:DiABZI 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, IFN gamma, 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.
CONCLUSIONS: Our 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.
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阻断HIF-1α/糖酵解轴通过降低ILC2代谢和功能抑制过敏性气道炎症
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哮喘-慢性阻塞性肺疾病重叠和嗜酸性粒细胞慢性阻塞性肺疾病中嗜酸性粒细胞的炎症特征：一项多组学研究
