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 FADD^AEC-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成为控制屏障表面免疫稳态的关键机制。坏死性凋亡是一种由受体相互作用蛋白激酶 3 (RIPK3) 诱导的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病理。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。在这里，我们展示了气道上皮细胞 (AEC) 特异性缺乏 Fas 与死亡结构域 (FADD) 相关的小鼠，这是一种对 caspase-8 激活必不可少的适配器，在由致敏和诱发的哮喘小鼠模型中发展为加重的过敏性气道炎症屋尘螨 (HDM) 提取物的挑战。^AEC-KO小鼠，表明 FADD 缺陷型 AEC 的坏死性凋亡增强了过敏性免疫反应。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，并表明坏死性凋亡可能导致呼吸道病毒感染引起的哮喘加重，从而导致 AEC 死亡。