Interleukin-26 potentiates type 2 skin inflammation in presence of interleukin-1β

Atopic dermatitis (AD) is a debilitating inflammatory skin disorder. Biologics targeting the IL-4/IL-13 axis are effective in AD, but there is still a large proportion of patients that do not respond to IL-4R blockade. Further exploration of potentially pathogenic T cell-derived cytokines in AD may lead to new effective treatments. This study aimed to investigate the downstream effects of IL-26 on skin in the context of type 2 skin inflammation. We found that IL-26 alone exhibited limited inflammatory activity in skin. However, in presence of IL-1β, IL-26 potentiated the secretion of TSLP, CXCL1 and CCL20 from human epidermis through JAK/STAT signaling. Moreover, in an in vivo AD-like skin inflammation model, IL-26 exacerbated skin pathology and locally increased type 2 cytokines, most notably of Il13 in skin T helper cells. Neutralization of IL-1β abrogated IL-26-mediated effects, indicating that the presence of IL-1β is required for full IL-26 downstream action in vivo. These findings suggest that the presence of IL-1β enables IL-26 to be a key amplifier of inflammation in the skin. As such, IL-26 may contribute to the development and pathogenesis of inflammatory skin disorders such as AD. Gene expression profiling analysis of RNA-seq data from samples obtained from mouse ear skin. Mice were chronically treated every 2-3 days for 17 days with 1.5 nmol MC903. Additionally, mice were treated i.p. with 10 mg/kg anti IL-1b or IgG control antibody every 5 days. Moreover, 200 ng recombinant human IL-26 or BSA as a control was injected into the ear skin of mice every 2 days.