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- W4386040693 abstract "Background: Pathogenic CRTh2+ T helper 2 (pTh2) cells are crucial contributors to the pathogenesis of atopic dermatitis (AD) by secreting high levels of interleukin (IL-)13 and IL-22. Yet, the upstream regulators of pTh2 cells in AD skin remain incompletely understood. IL-18 is one such putative regulator and is linked to AD pathogenesis by multiple lines of evidence raising intriguing questions regarding its role in the activation of pTh2 cells in AD skin. Objective & Methods: We sought to decipher the role of IL-18 in human Th2 responses in AD by analyzing pTh2 cells from AD patients, as well as ex vivo skin explants of human healthy and lesional AD skin. Results: We first investigated the signals that induce interleukin 18 receptor (IL-18R) expression on Th2 cells. Of all the cytokines for which pTh2 cells express the receptor, only IL-9 was able to induce high levels of IL-18R via a previously unknown TYK2/JAK1-STAT1 signaling pathway. Consistently, IL-9R+/IL-18R+ pTh2 cells were strongly increased in the peripheral blood of AD patients. Functionally, stimulation of circulating pTh2 cells with IL-18 induced secretion of IL-13 and IL-22, an effect that was significantly enhanced by co-stimulation with IL-9. Mechanistically, IL-18 induces rapid and strong activation of both NF-κB and AP-1 signaling in pTh2 cells. In human skin explants from lesional AD skin, neutralization of IL-18 rapidly downregulated both IL-13 and IL-22 secretion from pTh2 cells. Finally, IL-18 protein levels correlated positively with IL13expression in lesional skin of AD. Conclusion: Collectively, our data reveal a previously underappreciated role of IL-9 and IL-18 as positive regulators of Th2 cell responses in human AD. Further, we uncover a novel signaling cascade downstream of the IL-9R on pTh2 cells involving TYK2 and STAT1. These findings may guide future therapeutic approaches aiming at inhibiting aberrant activation of pTh2 cells in human skin." @default.
- W4386040693 created "2023-08-22" @default.
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- W4386040693 date "2023-09-01" @default.
- W4386040693 modified "2023-09-25" @default.
- W4386040693 title "LB1645 IL-9 sensitizes human pathogenic Th2 cells to pro-inflammatory IL-18 signals in atopic dermatitis" @default.
- W4386040693 doi "https://doi.org/10.1016/j.jid.2023.06.017" @default.
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