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

Autor: Schärli S; Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland., Luther F; Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland., Di Domizio J; Department of Dermatology, CHUV University Hospital, University of Lausanne, Lausanne, Switzerland., Hillig C; Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany., Radonjic-Hoesli S; Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland., Thormann K; Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland., Simon D; Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland., Møller Rønnstad AT; Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark., Ruge IF; Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark., Fritz BG; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark., Bjarnsholt T; Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Microbiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark., Vallone A; Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland., Kezic S; Department of Public and Occupational Health, Amsterdam University Medical Center, University of Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, Netherlands., Menden MP; Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany; Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia., Roesner LM; Department of Dermatology and Allergy, Hannover Medical School (MHH), Hannover, Germany., Werfel T; Department of Dermatology and Allergy, Hannover Medical School (MHH), Hannover, Germany., Thyssen JP; Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark., Eyerich S; Center for Allergy and Environment (ZAUM), Technical University and Helmholtz Center Munich, Munich, Germany., Gilliet M; Department of Dermatology, CHUV University Hospital, University of Lausanne, Lausanne, Switzerland., Bertschi NL; Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland., Schlapbach C; Department of Dermatology, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland. Electronic address: christoph.schlapbach@insel.ch.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2024 Nov 07. Date of Electronic Publication: 2024 Nov 07.
DOI: 10.1016/j.jaci.2024.10.027
Abstrakt: 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.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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