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Despite sharing interleukin‐4 receptor α (IL‐4Rα) in their signaling cascades, IL‐4 and IL‐13 have different functions in atopic inflammation. IL‐13 preferentially participates in the peripheral tissues because tissue‐resident group 2 innate lymphoid cells produce IL‐13 but not IL‐4. In contrast, lymph node T follicular helper cells express IL‐4 but not IL‐13 to regulate B‐cell immunity. The dominant microenvironment of IL‐13 is evident in the lesional skin of atopic dermatitis (AD). The IL‐13‐rich local milieu causes barrier dysfunction by down‐regulating the OVOL1–filaggrin (FLG) axis and up‐regulating the periostin–IL‐24 axis. Genome‐wide association studies also point to the crucial involvement of the IL‐13, OVOL1 and FLG genes in the pathogenesis of AD. Biologics targeting IL‐13, such as the anti‐IL‐4Rα antibody dupilumab and the anti‐IL‐13 antibody tralokinumab, successfully improve AD lesions and further highlight the importance of IL‐13 in the pathogenesis of AD.

To summarize recent topics on type 2 signatures in atopic dermatitis (AD). Therapeutic success of anti-IL-4 receptor antibody dupilumab does suggest that type 2 cytokines IL-4 and IL-13 have pivotal roles in the pathogenesis of AD. Lesional skin of AD expresses increased levels of IL-4 and IL-13. In parallel, type 2 chemokines such as CCL17, CCL22, and CCL26 are overexpressed in AD, and these chemokines recruit type 2 T cells and eosinophils. IL-4 and IL-13 downregulate the expression of filaggrin and exacerbate epidermal barrier dysfunction. Keratinocytes in barrier-disrupted epidermis produce thymic stromal lymphopoietin, IL-25 and IL-33, which enhance the type 2 immune response. IL-31, released from type 2 T cells, is an essential pruritogenic cytokine. IL-4 and IL-13 amplify the IL-31-mediated neuronal signal. Type 2 cytokines IL-4 and IL-13 are profoundly associated with three cardinal features of AD: barrier dysfunction, skin inflammation, and chronic pruritus. These findings explain the high efficacy of dupilumab in the treatment of AD.

Severe pruritus is a characteristic feature of atopic dermatitis (AD) and is closely related to its activity. Recent studies have shown that IL-31 is a key determinant of pruritus in AD. Anti-IL-31 receptor alpha (IL-31RA) antibody treatment has also been reported to improve pruritus clinically, subsequently contributing to the attenuation of AD disease activity. Therefore, IL-31 has been thought to be an important cytokine for regulating pruritus and AD disease activity, however, how IL-31 is involved in the immune response in AD has remained largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in AD pathogenesis. LCs and DCs produce Ccl 17 and Ccl 22, which chemoattract Th2 cells, leading to AD development. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects Ccl 17 and Ccl 22 production. To test this, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-4, an important cytokine in AD development. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-31 upregulates Ccl 17 and Ccl 22 production in the presence of IL-4, whereas IL-31 stimulation alone did not produce Ccl 17 and Ccl 22. These findings suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments Ccl 17 and Ccl 22 production in BMDCs, which promotes Th2-deviated immune response in AD. Since we previously reported that soybean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affects IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 stimulation in a dose-dependent manner. Glyteer also inhibited Ccl 17 and Ccl 22 production induced by IL-4 and IL-31 stimulation. Taken together, these findings suggest that Glyteer treatment may improve AD disease activity by impairing IL-31/IL-31RA interaction in DCs.

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.