Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) & Center for Molecular Medicine, University of Cologne, Cologne, Germany.
Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
Mucosal Immunol. 2021 Sep;14(5):1160-1171. doi: 10.1038/s41385-021-00415-5. Epub 2021 May 27.
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 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.
细胞死亡的调控已成为控制屏障表面免疫动态平衡的关键机制。坏死性凋亡是一种受受体相互作用蛋白激酶 3（RIPK3）诱导的调节性坏死细胞死亡，已被证明会在不同组织中引起炎症性病理。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知之甚少。在这里，我们发现气道上皮细胞（AEC）中 Fas 相关死亡结构域（FADD）的特异性缺乏，一种对于半胱天冬酶-8 激活至关重要的衔接蛋白，会导致对屋尘螨（HDM）提取物诱导的哮喘模型中的过敏气道炎症加剧。通过与表达激酶失活的 RIPK1 以及 RIPK3 或 MLKL 缺陷的小鼠杂交，抑制 RIPK1 激酶活性的遗传抑制，可预防 FADD 缺陷的 AEC 中发生的坏死性凋亡导致的 HDM 诱导的哮喘病理学的过度发展，表明 FADD 缺陷的 AEC 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诱导 AEC 死亡而引发哮喘恶化。
