屋尘螨致中性粒细胞哮喘急性发作的STING依赖性诱导
2024/11/29
摘要
背景：重症难治性中性粒细胞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激活可能导致中性粒细胞急性发作。我们的目的是确定STING诱导的中性粒细胞肺部炎症是否与严重哮喘相似。
方法：我们开发了由屋尘螨（HDM）和STING激动剂二氨基苯并咪唑（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肺部炎症的新模型。我们通过免疫印迹测量了DNA损伤、细胞死亡、NETs、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，通过多重检测了Th1/Th2细胞因子。我们评估了diABZI对健康人或哮喘患者气道上皮细胞的影响，并通过鼻病毒感染的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攻击期间服用DiABZI会增加气道高反应性、中性粒细胞募集和NOS2ARG1 1型中性粒细胞、蛋白质外渗、PANoptosis引起的细胞死亡、NETs形成、细胞外dsDNA释放、DNA传感器激活、IFNγ、IL-6和CXCL10释放。从功能上讲，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STING通路激活，与哮喘患者鼻病毒攻击诱导的DNA传感和PANoptosis通路上调和紧密连接下调一致。
结论：我们的研究发现，在哮喘背景下触发STING会诱导PANoptosis引起的细胞死亡，通过Th1/Th2混合免疫反应助长炎症反应，这概括了具有1型中性粒细胞预后特征的重症哮喘的特征。
STING-dependent induction of neutrophilic asthma exacerbation in response to house dust mite
Yasmine Messaoud-Nacer, Elodie Culerier, Stéphanie Rose, Isabelle Maillet, Rania Boussad, Chloé Veront, Florence Savigny, Bernard Malissen, Urszula Radzikowska, Milena Sokolowska, Gabriel V L da Silva, Michael R Edwards, David J Jackson, Sebastian L Johnston, Bernhard Ryffel, Valerie F Quesniaux, Dieudonnée Togbe
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 NOS2ARG1 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. +-
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：重症难治性中性粒细胞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激活可能导致中性粒细胞急性发作。我们的目的是确定STING诱导的中性粒细胞肺部炎症是否与严重哮喘相似。
方法：我们开发了由屋尘螨（HDM）和STING激动剂二氨基苯并咪唑（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肺部炎症的新模型。我们通过免疫印迹测量了DNA损伤、细胞死亡、NETs、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，通过多重检测了Th1/Th2细胞因子。我们评估了diABZI对健康人或哮喘患者气道上皮细胞的影响，并通过鼻病毒感染的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攻击期间服用DiABZI会增加气道高反应性、中性粒细胞募集和NOS2ARG1 1型中性粒细胞、蛋白质外渗、PANoptosis引起的细胞死亡、NETs形成、细胞外dsDNA释放、DNA传感器激活、IFNγ、IL-6和CXCL10释放。从功能上讲，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STING通路激活，与哮喘患者鼻病毒攻击诱导的DNA传感和PANoptosis通路上调和紧密连接下调一致。
结论：我们的研究发现，在哮喘背景下触发STING会诱导PANoptosis引起的细胞死亡，通过Th1/Th2混合免疫反应助长炎症反应，这概括了具有1型中性粒细胞预后特征的重症哮喘的特征。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Allergy. 2024 Oct 28. doi: 10.1111/all.16369.)
(Allergy. 2024 Oct 28. doi: 10.1111/all.16369.)
STING-dependent induction of neutrophilic asthma exacerbation in response to house dust mite
Yasmine Messaoud-Nacer, Elodie Culerier, Stéphanie Rose, Isabelle Maillet, Rania Boussad, Chloé Veront, Florence Savigny, Bernard Malissen, Urszula Radzikowska, Milena Sokolowska, Gabriel V L da Silva, Michael R Edwards, David J Jackson, Sebastian L Johnston, Bernhard Ryffel, Valerie F Quesniaux, Dieudonnée Togbe
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 NOS2ARG1 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. +-
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.
上一篇：
抗体介导的免疫反应对慢性阻塞性肺病、哮喘和肺功能的影响： 孟德尔随机化研究
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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
