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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1160-1171
Number of pages12
JournalMucosal Immunology
Volume14
Issue number5
DOIs
Publication statusPublished - Sep 2021

Bibliographical note

Funding Information:
We thank E. Gareus, J. Kuth, B. Kühnel, E. Stade, C. Uthoff-Hachenberg and J. von Rhein for technical assistance. We are grateful to V. Dixit and Genentech for providing Ripk3−/− mice. M.P. acknowledges funding from the Deutsche Forschungsge-meinschaft (DFG, German Research Foundation; projects PA 1476/6-1 (project no.), SFB1403 (project no. 414786233), and under Germany’s Excellence Strategy–EXC 2030 CECAD (project no. 390661388).

Publisher Copyright:
© 2021, The Author(s).

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