1. Airway epithelial cell necroptosis contributes to asthma exacerbation in a mouse model of house dust mite-induced allergic inflammation
- Author
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Nikos Oikonomou, Manolis Pasparakis, Ariadne Androulidaki, Hamida Hammad, Antonis Chatzigiagkos, Vassilis Aidinis, Bart N. Lambrecht, Martjin J Schuijs, and Pulmonary Medicine
- Subjects
0301 basic medicine ,HOMEOSTASIS ,Fas-Associated Death Domain Protein ,Mice ,0302 clinical medicine ,Medicine and Health Sciences ,Basic Helix-Loop-Helix Transcription Factors ,Immunology and Allergy ,Medicine ,FADD ,Mice, Knockout ,biology ,Pyroglyphidae ,DEATH ,TRIGGERS ,respiratory system ,Immunohistochemistry ,APOPTOSIS ,Receptor-Interacting Protein Serine-Threonine Kinases ,030220 oncology & carcinogenesis ,Necroptosis ,Disease Progression ,Airway Remodeling ,Respiratory virus ,Disease Susceptibility ,EXPRESSION ,Immunology ,INTERLEUKIN-1-ALPHA ,Respiratory Mucosa ,IMMUNITY ,Article ,Allergic inflammation ,03 medical and health sciences ,RIPK1 ,CASPASE-8 ,Animals ,Humans ,Kinase activity ,Death domain ,RELEASE ,House dust mite ,business.industry ,Biology and Life Sciences ,Allergens ,Immunoglobulin E ,biology.organism_classification ,Asthma ,Enzyme Activation ,Disease Models, Animal ,030104 developmental biology ,Receptors, Aryl Hydrocarbon ,CREOLA BODIES ,biology.protein ,business ,Biomarkers - 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.
- Published
- 2021