Inhibition of DYRK1B suppresses inflammation in allergic contact dermatitis model and Th1/Th17 immune response

Abstract

Allergic contact dermatitis (ACD) is a type IV hypersensitivity mainly mediated by Th1/Th17 immune response. Topical corticosteroid is currently the first-line treatment for allergic contact dermatitis (ACD) and systemic administration of immunosuppressive drugs are used in patients with severe disseminated cases. However, increased risk of adverse effects has limited their use. Thus, the development of a novel immunosuppressant for ACD with low toxicity is a challenging issue. In this study, we began our study by using a murine contact hypersensitivity (CHS) model of ACD to examine the immunosuppressive effects of DYRK1B inhibition. We found that mice treated with a selective DYRK1B inhibitor show reduced ear inflammation. In addition, a significant reduction of Th1 and Th17 cells in the regional lymph node upon DYRK1B inhibition was observed by FACS analysis. Studies in vitro further revealed that DYRK1B inhibitor does not only suppressed Th1 and Th17 differentiation, but also promotes regulatory T cells (Treg) differentiation. Mechanistically, FOXO1 signaling was enhanced due to the suppression of FOXO1Ser329 phosphorylation in the presence of DYRK1B inhibitor. Therefore, these findings suggest that DYRK1B regulates CD4 T cell differentiation through FOXO1 phosphorylation and DYRK1B inhibitor has a potential as a novel agent for treatment of ACD.

Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics

“…In line with our findings, targeting type-1 immune response has emerged as effective therapeutic approach against allergic skin diseases (Liu et al, 2023; Wongchang et al, 2023; Wu et al, 2021). Interferon signaling, including IFNγ signaling, has been identified as a highly enriched pathway during nickel-induced contact allergy in humans (Wisgrill et al, 2021).…”

“…In line with our findings, targeting type-1 immune response has emerged as effective therapeutic approach against allergic skin diseases (Liu et al, 2023;Wongchang et al, 2023;Wu et al, 2021).…”

“…Our results indicate that the type-1 inflammation observed upon ACD elicitation is predominantly driven by memory T cells recruited from lymphoid organs, rather than by skin resident memory T cells. However, other studies have shown that when the later elicitation phase is conducted on the same skin area as the initial sensitization, it results in a rapid allergen-induced skin inflammatory response, that is primarily mediated by IL17A-producing and IFNγ-producing CD8 + skin resident memory T cells 43,[50][51][52] . These studies suggest that Trm cells establish a long-lasting local memory during the initial sensitization, and upon re-exposure to the hapten in the same skin area, these site-specific Trm cells can rapidly contribute to a robust type-1 skin inflammatory response.…”