IL-9 sensitizes human TH2 cells to proinflammatory IL-18 signals in atopic dermatitis
Stefanie Schärli, Fabian Luther, Jérémy Di Domizio, Christina Hillig, Susanne Radonjic‐Hoesli, Kathrin Thormann, Dagmar Simon, Amalie Thorsti Møller Rønnstad, Iben Frier Ruge, Blaine Gabriel Fritz, Thomas Bjarnsholt, Angela Vallone, Sanja Kežić, Michael P. Menden, Lennart M. Roesner, Thomas Werfel, Jacob P. Thyssen, Stefanie Eyerich, Michel Gilliet, Nicole Bertschi, Christoph Schlapbach
Abstract
Background T H 2 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 T H 2 cells in AD skin remain unclear. IL-18 is a putative upstream regulator of T H 2 cells because it is implicated in AD pathogenesis and has the capacity to activate T cells. Objective We sought to decipher the role of IL-18 in T H 2 responses in blood and skin of AD patients. Methods Peripheral blood mononuclear cells and skin biopsy samples from AD patients and healthy donors were used. Functional assays were performed ex vivo using stimulation or blocking experiments. Analysis was performed by flow cytometry, bead-based multiplex assays, RT-qPCR, RNA-Seq, Western blot, and spatial sequencing. Results IL-18Rα + T H 2 cells were enriched in blood and lesional skin of AD patients. Of all the cytokines for which T H 2 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 T H 2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was enhanced by costimulation with IL-9. Mechanistically, IL-18 induced T H 2 cytokines via activation of IRAK4, NF-κB, and AP-1 signaling in T H 2 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 T H 2 responses in AD. Our findings suggest that both IL-9 and IL-18 could represent upstream targets for future treatment of AD.