IL-19 Exacerbates Atopic Dermatitis by Disrupting Epidermal Barrier Function and Amplifying Type 2 Inflammation

Atopic dermatitis (AD) is a highly heterogeneous chronic inflammatory skin disease, and the exact role and mechanisms of interleukin (IL)-19 in AD remain unclear. This study integrated serum samples from AD patients, transcriptomic data from clinical AD lesions, AD-like mouse models with exogenous IL-19 supplementation or IL-19 gene knockout, and in vitro cellular models to investigate its mechanism of action. Serum IL-19 levels correlated with disease severity after adjustment for clinical covariates and type 2 cytokines in this cohort. In an MC903-induced AD-like mouse model, exogenous IL-19 supplementation exacerbated the dermatitis phenotype, whereas IL-19 gene knockout alleviated it. Mechanistically, keratinocytes constituted the primary source of IL-19 within AD lesions, with house dust mites inducing its upregulation in these cells in vitro. IL-19 acted through the STAT6/STAT3 signaling pathway to suppress loricrin and keratin-10 expression, which may result in epidermal barrier impairment. Simultaneously, it upregulated thymic stromal lymphopoietin and IL-33, potentially facilitating the type 2 inflammatory cascade in AD. Furthermore, IL-19 may additively exacerbate inflammatory responses with IL-13 and IL-4. Collectively, these findings support a role for IL-19 as a pro-inflammatory mediator in AD, suggesting that IL-19 contributes to both epidermal barrier dysfunction and type 2 immune dysregulation in this disease.