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Distinct Roles of IL-4, IL-13, and IL-22 in Human Skin Barrier Dysfunction and Atopic Dermatitis

ABSTRACT: Atopic dermatitis (AD) is a chronic type-2 inflammatory skin disease characterized by epithelial barrier dysfunction. IL-4, IL-13, and IL-22 represent major cytokines contributing to AD-pathogenesis. Models using reconstructed keratinocytes have been used in previous studies, however, did not represent the real skin situation. Here, we report the distinct effects of IL-4, IL-13, and IL-22 on bio-stabilized human skins with intact barriers and resident immune cells. Spatial transcriptomics on AD-lesions and non-lesional skin of patients, and RNA-sequencing, and proteomics were performed in IL-4-, IL-13- and IL-22-treated native skins. Skin barrier integrity was evaluated using electrical impedance spectroscopy. Spatial transcriptomics demonstrated that CLDN1, FLG, and FLG2 were significantly downregulated in the epidermis of AD lesions. IL-4, IL-13, and IL-22 disrupted the skin barrier in the ex vivo human skin by downregulation of the genes and proteins critical for barrier function and keratinization. IL-4 and IL-13 suppressed, whereas IL-22 upregulated the antimicrobial peptides. Interestingly, IL-4 and IL-13 showed a cross-regulation with IL-22, by downregulation of IL-22Rα1 with IL-4 and IL-13 and upregulation of IL-4Rα with IL-22. Three months of dupilumab treatment in AD patients restored the IL-4 and IL-13-dysregulated genes, whereas genes co-regulated or only regulated by IL-22 remained unaltered. In conclusion, this study comprehensively provides insights into the distinct immune profiles following IL-4, IL-13, and IL-22 stimulation in human skin, highlighting their complex interplay in the pathogenesis of AD modulating keratinocyte and immune responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292848 | GEO | 2025/12/05

REPOSITORIES: GEO

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Project description:In atopic dermatitis (AD), epidermal disease hallmarks are driven by a complex cutaneous inflammatory milieu that varies between patients. How these variable inflammatory signatures translate to patient-specific disease endotypes is poorly understood, which hampers the personalized use of targeted drugs. We here employed primary and immortalized keratinocyte-derived human epidermal equivalents stimulated with T helper (Th)2, -17 and -22 cytokines, to unravel which AD-associated cytokines drive specific epidermal disease hallmarks. Th2 cytokines IL-4 and IL-13 were main inducers of a pro-inflammatory and hyperproliferative response. The presence of IL-17A or IL-22 in the Th2 milieu caused spongiosis, impaired keratinocyte differentiation (loss of FLG, IVL, KRT2) and epidermal barrier defects (altered CLDN1, CLDN4, transepithelial impedance). Transcriptomic analyses revealed upregulation of proliferation genes by Th2 cytokines, and activation of different immune pathways upon Th2 cytokines alone and combination of Th2 and Th17/22 cytokines. Downregulation of epidermis development was most apparent upon combined exposure to Th2 cytokines and IL-22. Single-cell spatial transcriptomics showed expansion of keratinocytes expressing high level of proliferation genes in all epidermal layers, and downregulation of terminal differentiation genes in the upper epidermal layers. Our in vitro AD model using Th2 + IL-22 showed the highest transcriptome resemblance with in vivo AD lesional epidermis and we identified IL-22 specific alteration of epidermis development by lipid mediators like ACER1 and AKR1C3. Finally, we revealed that Aryl Hydrocarbon Receptor (AHR) ligands partially restored the barrier defects caused by Th2 and IL-22, whereas combination of AHR ligand Tapinarof with Janus Kinase (JAK) inhibitor I had an even greater restoring effect. Thus, specific combinations of cytokines upregulated in AD skin drive differential disease hallmarks highlighting the importance of personalized medicine and the need for prediction models in the targeted treatment of AD patients.

Project description:Atopic dermatitis (AD) is a common disease, with an increasing prevalence. The primary pathogenesis of the disease is still elusive, resulting in lack of specific treatments. The prevailing view is that AD is a biphasic, T-cell polarized disease, with Th2 predominating acute AD, and a switch to Th1 characterizing chronic disease. Identification of factors that participate in onset of lesions and maintenance of chronic lesions is critical for development of targeted therapeutics. We performed global genomic, molecular and cellular profiling of paired non-lesional, acute, and chronic skin biopsies from ten AD patients. Onset of acute lesions is associated with a striking increase in a subset of terminal differentiation proteins, specifically the IL-22-modulated S100A7-9. Correspondingly, acute disease is associated with significant increases in gene expression levels of the major Th22- (IL-22) and Th2- (IL-4, IL-31) cytokines and Th17-regulated genes (CCL20, PI3/Elafin), without significant changes in IL-17. A lesser induction of Th1- (IFNγ, MX-1, CXCL9-11) associated genes was detected in acute disease. Chronic skin lesions are characterized by significantly intensified activation of Th22, Th2 and Th1. Our data establish increased expression of S100A7-9 and other epidermal genes at onset of acute AD, with parallel activation of Th2 and Th22 cytokines. Our findings suggest an absence of switch mechanism in chronic disease and instead indicate that progression to chronic lesions is associated with intensified activation of immune axes that initiate onset of acute lesions, particularly Th22 and Th2. This alters the prevailing view of pathogenesis, with important therapeutic implications. Acute, chronic, and non-lesional skin samples were collected from ten patients with moderate-to-severe AD that met our inclusion criteria, under an institutional review board–approved protocol. The following criteria were employed to define acute AD and distinguish true acute from “acute on chronic” skin lesions: a) new lesions of <72 hours duration, as previously defined;14 b) lack of skin lichenification; c) lack of regenerative hyperplasia, as defined by epidermal thickness ≤150μ [hematoxylin and eosin (H&E)] and basal or confluent supra-basal Keratin 16 (K16) positivity. No systemic or topical treatments were allowed for ≥4 weeks prior to biopsies. Biopsy specimens were frozen in optimal cutting temperature (OCT) for immunohistochemistry (IHC) and liquid nitrogen for RNA extraction.

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Distinct Roles of IL-4, IL-13, and IL-22 in Human Skin Barrier Dysfunction and Atopic Dermatitis

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