气道上皮细胞坏死性凋亡导致屋尘螨诱导的过敏性炎症小鼠模型的哮喘恶化
2021/06/18
摘要
上皮细胞死亡的调节已经成为控制屏障表面免疫稳态的关键机制。坏死性凋亡是由受体相互作用蛋白激酶3（RIPK3）诱导的一种受调节的坏死细胞死亡，已被证明会在不同组织中引起炎症。调节性细胞死亡，特别是坏死性凋亡在肺稳态和疾病中的作用仍然知之甚少。我们使用气道上皮细胞（AEC）特异性缺乏Fas死亡相关结构域（FADD，一种caspase-8激活必不可少的适配器）的小鼠，经屋尘螨（HDM）提取物致敏和诱导成急性过敏性气道炎症哮喘小鼠模型。在FADDAEC-KO小鼠中，通过与表达激酶失活的RIPK1以及RIPK3或MLKL缺陷的小鼠杂交对RIPK1激酶活性的基因抑制，可以阻止HDM诱导的哮喘病理的发展，表明FADD缺陷型AEC的坏死性凋亡增强了过敏免疫反应。这些结果揭示了AEC坏死性凋亡在放大气道过敏性炎症中的作用，并且表明由呼吸道病毒感染导致的AEC坏死性凋亡可引起哮喘恶化。
Airway epithelial cell necroptosis contributes to asthma exacerbation in a mouse model of house dust mite-induced allergic inflammation
Nikos Oikonomou, Martjin J Schuijs, Antonis Chatzigiagkos, Ariadne Androulidaki, Vassilis Aidinis, Hamida Hammad, Bart N Lambrecht, Manolis Pasparakis
Abstract
Regulation of epithelial cell death has emerged as a key mechanism controlling immune homeostasis in barrier surfaces. Necroptosis is a type of regulated necrotic cell death induced by receptor interacting protein kinase 3 (RIPK3) that has been shown to cause inflammatory pathologies in different tissues. The role of regulated cell death and particularly necroptosis in lung homeostasis and disease remains poorly understood. Here we show that mice with Airway Epithelial Cell (AEC)-specific deficiency of Fas-associated with death domain (FADD), an adapter essential for caspase-8 activation, developed exacerbated allergic airway inflammation in a mouse model of asthma induced by sensitization and challenge with house dust mite (HDM) extracts. Genetic inhibition of RIPK1 kinase activity by crossing to mice expressing kinase inactive RIPK1 as well as RIPK3 or MLKL deficiency prevented the development of exaggerated HDM-induced asthma pathology in FADDAEC-KO mice, suggesting that necroptosis of FADD-deficient AECs augmented the allergic immune response. These results reveal a role of AEC necroptosis in amplifying airway allergic inflammation and suggest that necroptosis could contribute to asthma exacerbations caused by respiratory virus infections inducing AEC death.
上皮细胞死亡的调节已经成为控制屏障表面免疫稳态的关键机制。坏死性凋亡是由受体相互作用蛋白激酶3（RIPK3）诱导的一种受调节的坏死细胞死亡，已被证明会在不同组织中引起炎症。调节性细胞死亡，特别是坏死性凋亡在肺稳态和疾病中的作用仍然知之甚少。我们使用气道上皮细胞（AEC）特异性缺乏Fas死亡相关结构域（FADD，一种caspase-8激活必不可少的适配器）的小鼠，经屋尘螨（HDM）提取物致敏和诱导成急性过敏性气道炎症哮喘小鼠模型。在FADDAEC-KO小鼠中，通过与表达激酶失活的RIPK1以及RIPK3或MLKL缺陷的小鼠杂交对RIPK1激酶活性的基因抑制，可以阻止HDM诱导的哮喘病理的发展，表明FADD缺陷型AEC的坏死性凋亡增强了过敏免疫反应。这些结果揭示了AEC坏死性凋亡在放大气道过敏性炎症中的作用，并且表明由呼吸道病毒感染导致的AEC坏死性凋亡可引起哮喘恶化。
(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)
(Mucosal Immunol. 2021 May 27. doi: 10.1038/s41385-021-00415-5.)
(Mucosal Immunol. 2021 May 27. doi: 10.1038/s41385-021-00415-5.)
Airway epithelial cell necroptosis contributes to asthma exacerbation in a mouse model of house dust mite-induced allergic inflammation
Nikos Oikonomou, Martjin J Schuijs, Antonis Chatzigiagkos, Ariadne Androulidaki, Vassilis Aidinis, Hamida Hammad, Bart N Lambrecht, Manolis Pasparakis
Abstract
Regulation of epithelial cell death has emerged as a key mechanism controlling immune homeostasis in barrier surfaces. Necroptosis is a type of regulated necrotic cell death induced by receptor interacting protein kinase 3 (RIPK3) that has been shown to cause inflammatory pathologies in different tissues. The role of regulated cell death and particularly necroptosis in lung homeostasis and disease remains poorly understood. Here we show that mice with Airway Epithelial Cell (AEC)-specific deficiency of Fas-associated with death domain (FADD), an adapter essential for caspase-8 activation, developed exacerbated allergic airway inflammation in a mouse model of asthma induced by sensitization and challenge with house dust mite (HDM) extracts. Genetic inhibition of RIPK1 kinase activity by crossing to mice expressing kinase inactive RIPK1 as well as RIPK3 or MLKL deficiency prevented the development of exaggerated HDM-induced asthma pathology in FADDAEC-KO mice, suggesting that necroptosis of FADD-deficient AECs augmented the allergic immune response. These results reveal a role of AEC necroptosis in amplifying airway allergic inflammation and suggest that necroptosis could contribute to asthma exacerbations caused by respiratory virus infections inducing AEC death.
