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. 2025 Sep;156(3):690-704.
doi: 10.1016/j.jaci.2025.05.007. Epub 2025 May 21.

Dissecting key contributions of TH2 and TH17 cytokines to atopic dermatitis pathophysiology

Luca D Meesters  1 , Janou A Y Roubroeks  2 , Aranka Gerritsen  3 , Niels Velthuijs  4 , Jaimy A Klijnhout  3 , Camille Laberthonnière  5 , Ivonne M van Vlijmen-Willems  3 , Matthias Hübenthal  6 , Diana Rodijk-Olthuis  3 , Rens H W Peters  3 , Gijs Rikken  3 , Silke Szymczak  7 , Nanna Fyhrquist  8 , Harri Alenius  9 , Stephan Weidinger  6 , Jos P H Smits  10 , Musa Mhlanga  11 , Huiqing Zhou  12 , Hanna Niehues  3 , Ellen H van den Bogaard  13
Affiliations

Dissecting key contributions of TH2 and TH17 cytokines to atopic dermatitis pathophysiology

Luca D Meesters et al. J Allergy Clin Immunol. 2025 Sep.

Abstract

Background: 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.

Objective: We aimed to unravel which AD-associated cytokines drive specific epidermal disease hallmarks.

Methods: We utilized primary and immortalized keratinocyte-derived human epidermal equivalents stimulated with TH2, TH17, and TH22 cytokines.

Results: Morphologic, functional, and transcriptomic analyses revealed that TH2 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 TH2 milieu, and especially TH2 + 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 TH2 + IL-22 AD model demonstrated greatest resemblance and identified AD disease marker genes altered by TH2 + 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.

Conclusion: Our results reveal the important role of IL-22 in the TH2-driven acute AD pathophysiology and highlight the potential of combinatory medicine in targeted treatment of AD.

Keywords: Atopic dermatitis; keratinocytes; skin barrier; tapinarof; tofacitinib.

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Conflict of interest statement

Disclosure statement Supported by Health Holland grant PAST4FUTURE, LSHM20043-HSGF to E.B. and H.Z. Further support was provided to E.B. by Next Generation ImmunoDermatology (NGID) NWA-ORC project NWA.1389.20.182, EIC-Pathfinder project SKINDEV (no. 101098826), and LEO Foundation grant LF-OC-22-001056 to J.S. and E.B. E.B., M.H., and H.N. are funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 821511. The JU receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. This work reflects only the authors’ view, and the IMI 2 JU is not responsible for any use that may be made of the information it contains. Data availability: Raw RNA-Seq files generated for this study are deposited in the Gene Expression Omnibus (GEO; www.ncbi.nlm.nih.gov/geo) database under accession number GSE282371. Public transcriptomic datasets incorporated in the differential meta-analysis are available from ArrayExpress (accession E-MTAB-8149) and GEO (accession nos. GSE130588 and GSE193309). Data from P2N_clinical will be shared on reasonable request. Meta-analysis summary statistics are provided in Table E9 in this article’s Online Repository at www.jacionline.org. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.