Meesters Luca D, Roubroeks Janou A Y, Gerritsen Aranka, Velthuijs Niels, Klijnhout Jaimy A, Laberthonnière Camille, van Vlijmen-Willems Ivonne M, Hübenthal Matthias, Rodijk-Olthuis Diana, Peters Rens H W, Rikken Gijs, Szymczak Silke, Fyhrquist Nanna, Alenius Harri, Weidinger Stephan, Smits Jos P H, Mhlanga Musa, Zhou Huiqing, Niehues Hanna, van den Bogaard Ellen H
Department of Dermatology, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands; Department of Molecular Developmental Biology, Faculty of Science, Radboud University, Nijmegen, The Netherlands.
Department of Molecular Developmental Biology, Faculty of Science, Radboud University, Nijmegen, The Netherlands.
J Allergy Clin Immunol. 2025 May 21. doi: 10.1016/j.jaci.2025.05.007.
In atopic dermatitis (AD), epidermal disease hallmarks are driven by a complex cutaneous inflammatory milieu that varies between patients. How these variable inflammatory signals affect cellular and molecular epidermal AD phenotypes is difficult to study in vivo.
We aimed to unravel which AD-associated cytokines drive specific epidermal disease hallmarks.
We utilized primary and immortalized keratinocyte-derived human epidermal equivalents stimulated with T2, T17, and T22 cytokines.
Morphologic, functional, and transcriptomic analyses revealed that T2 cytokines IL-4 and IL-13 were the main inducers of a proinflammatory and hyperproliferative epidermis. The presence of IL-17A or IL-22 in the T2 milieu, and especially T2 + IL-22, most closely resembled AD hallmarks including spongiosis, more severe keratinocyte differentiation defects, and epidermal barrier dysfunction. Single-cell spatial transcriptomics showed expansion of keratinocytes expressing high levels of proliferation genes and downregulation of differentiation genes in the upper epidermal layers. The transcriptomic comparison to in vivo AD lesional skin indicated that the T2 + IL-22 AD model demonstrated greatest resemblance and identified AD disease marker genes altered by T2 + IL-22 such as downregulated ACER1 and AKR1C3. Gene expression levels were restored by combinatory exposure to the aryl hydrocarbon receptor ligand tapinarof and the Janus kinase inhibitor tofacitinib. This combined therapeutic approach also completely restored epidermal barrier function and improved morphologic disease hallmarks.
Our results reveal the important role of IL-22 in the T2-driven acute AD pathophysiology and highlight the potential of combinatory medicine in targeted treatment of AD.
在特应性皮炎（AD）中，表皮疾病特征由复杂的皮肤炎症环境驱动，这种环境在患者之间存在差异。在体内很难研究这些可变的炎症信号如何影响细胞和分子水平的表皮AD表型。
我们旨在阐明哪些与AD相关的细胞因子驱动特定的表皮疾病特征。
我们使用了用T2、T17和T22细胞因子刺激的原代表皮角质形成细胞和永生化表皮角质形成细胞衍生的人表皮替代物。
形态学、功能和转录组学分析表明，T2细胞因子IL-4和IL-13是促炎和过度增殖表皮的主要诱导因子。在T2环境中存在IL-17A或IL-22，尤其是T2 + IL-22，与AD特征最为相似，包括海绵形成、更严重的角质形成细胞分化缺陷和表皮屏障功能障碍。单细胞空间转录组学显示，在上层表皮中，表达高水平增殖基因的角质形成细胞扩张，分化基因下调。与体内AD皮损皮肤的转录组比较表明，T2 + IL-22 AD模型表现出最大的相似性，并鉴定出受T2 + IL-22改变的AD疾病标记基因，如下调的ACER1和AKR1C3。通过联合暴露于芳烃受体配体他扎罗汀和Janus激酶抑制剂托法替布，基因表达水平得以恢复。这种联合治疗方法还完全恢复了表皮屏障功能，并改善了形态学疾病特征。
我们的结果揭示了IL-22在T2驱动的急性AD病理生理学中的重要作用，并突出了联合药物在AD靶向治疗中的潜力。
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