IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis

Stefanie Schärli, Fabian Luther, Jeremy Di Domizio, Christina Hillig, Susanne Radonjic-Hoesli, Kathrin Thormann, Dagmar Simon, Amalie Thorsti Møller Rønnstad, Iben Frier Ruge, Blaine G Fritz, Thomas Bjarnsholt, Angela Vallone, Sanja Kezic, Michael P Menden, Lennart M Roesner, Thomas Werfel, Jacob P Thyssen, Stefanie Eyerich, Michel Gilliet, Nicole L BertschiChristoph Schlapbach*

*Corresponding author af dette arbejde

Abstract

BACKGROUND: T helper 2 (Th2) cells crucially contribute to the pathogenesis of atopic dermatitis (AD) by secreting high levels of IL-13 and IL-22. Yet, the upstream regulators that activate Th2 cells in AD skin remain unclear. IL-18 is a putative upstream regulator of Th2 cells as it is implicated in AD pathogenesis and has the capacity to activate T cells.

OBJECTIVE: To decipher the role of IL-18 in Th2 responses in blood and skin of AD patients.

METHODS: PBMCs and skin biopsies from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed using flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-seq, western blotting, and spatial sequencing.

RESULTS: IL-18Rα+ Th2 cells were enriched in blood and lesional skin of AD patients. Of all the cytokines for which Th2 cells express the receptor, only IL-9 was able to induce IL-18R via an IL-9R-JAK1/JAK3-STAT1 signaling pathway. Functionally, stimulation of circulating Th2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was enhanced by co-stimulation with IL-9. Mechanistically, IL-18 induced Th2 cytokines via activation of IRAK4, NF-κB, and AP-1 signaling in Th2 cells, and neutralization of IL-18 inhibited these cytokines in cultured explants of AD skin lesions. Finally, IL-18 protein levels correlated positively with disease severity in lesional AD skin.

CONCLUSION: Our data identify a novel IL-9-IL-18 axis that contributes to Th2 responses in AD. Our findings suggest that both IL-9 and IL-18 could represent upstream targets for future treatment of AD.

OriginalsprogEngelsk
TidsskriftThe Journal of allergy and clinical immunology
ISSN0091-6749
DOI
StatusE-pub ahead of print - 7 nov. 2024

Fingeraftryk

Dyk ned i forskningsemnerne om 'IL-9 sensitizes human Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis'. Sammen danner de et unikt fingeraftryk.

Citationsformater