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.

中文翻译：

---

IL-9 使特应性皮炎中的人 Th2 细胞对促炎性 IL-18 信号敏感。


背景 辅助性 T 细胞 2 （Th2） 通过分泌高水平的 IL-13 和 IL-22 对特应性皮炎 （AD） 的发病机制起关键作用。然而，激活 AD 皮肤中 Th2 细胞的上游调节因子仍不清楚。IL-18 是 Th2 细胞的推定上游调节因子，因为它与 AD 发病机制有关，并且具有激活 T 细胞的能力。目的 破读 IL-18 在 AD 患者血液和皮肤 Th2 反应中的作用。方法 使用 AD 患者和健康供体的 PBMC 和皮肤活检。使用刺激或阻断实验在离体进行功能测定。使用流式细胞术、基于微珠的多重检测、RT-qPCR、RNA-seq、western blotting 和空间测序进行分析。结果 IL-18Rα+ Th2 细胞在 AD 患者血液和病变皮肤中富集。在 Th2 细胞表达受体的所有细胞因子中，只有 IL-9 能够通过 IL-9R-JAK1/JAK3-STAT1 信号通路诱导 IL-18R。在功能上，IL-18 刺激循环 Th2 细胞诱导 IL-13 和 IL-22 的分泌，这种作用通过与 IL-9 的共刺激而增强。从机制上讲，IL-18 通过激活 Th2 细胞中的 IRAK4、NF-κB 和 AP-1 信号传导诱导 Th2 细胞因子，而 IL-18 的中和抑制了 AD 皮肤病变培养外植体中的这些细胞因子。最后，IL-18 蛋白水平与病变性 AD 皮肤的疾病严重程度呈正相关。结论 我们的数据确定了一种新的 IL-9-IL-18 轴，它有助于 AD 中的 Th2 反应。我们的研究结果表明，IL-9 和 IL-18 都可能代表未来治疗 AD 的上游靶点。