Rolle inflammatorischer und Zelltod-Signalwege in Lungenepithel- und Lungenmesenchymzellen für die Steuerung der Typ 2-Immunantwort und Pathogenese allergischer Atemwegsentzündungen
Zusammenfassung der Projektergebnisse
Necroptosis is a type of regulated necrotic cell death induced by receptor interacting protein kinase 3 (RIPK3) and its substrate Mixed Lineage Kinase Like (MLKL), which has been shown to cause inflammatory pathologies in different tissues. Regulated cell death has emerged as a key mechanism controlling immune homeostasis in barrier surfaces such as the skin and the gut, however the role of regulated cell death and particularly necroptosis in lung homeostasis and disease remains poorly understood. The main objective of the project was to investigate the role of regulated cell death and particularly necroptosis in lung homeostasis and disease. We found 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 deficiency prevented the development of exaggerated HDM-induced asthma pathology in FADDAEC-KO mice, suggesting that necroptosis of FADD-deficient AECs causes an exacerbation of the allergic immune response. These results reveal a role of necroptosis in amplifying airway allergic inflammation and suggest that necroptosis could contribute to asthma exacerbations caused by respiratory virus infections inducing AEC death. These results also introduce the rationale of using RIPK1 inhibitors for the treatment of asthma exacerbations.
