IL-25 enhances TH17 cell–mediated contact dermatitis by promoting IL-1β production by dermal dendritic cells

Background In addition to thymic stromal lymphopoietin and IL-33, IL-25 is known to induce T H 2 cytokine production by various cell types, including T H 2 cells, T H 9 cells, invariant natural killer T cells, and group 2 innate lymphoid cells, involved in T H 2-type immune responses. Because both T H 2-type and T H 17-type cells/cytokines are crucial for contact hypersensitivity (CHS), IL-25 can contribute to this by enhancing T H 2-type immune responses. However, the precise role of IL-25 in the pathogenesis of fluorescein isothiocyanate–induced CHS is poorly understood. Objective We investigated the contribution of IL-25 to CHS using Il25 −/− mice. Methods CHS was evaluated by means of measurement of ear skin thickness in mice after fluorescein isothiocyanate painting. Skin dendritic cell (DC) migration, hapten-specific T H cell differentiation, and detection of IL-1β–producing cells were determined by using flow cytometry, ELISA, and immunohistochemistry, respectively. Results In contrast to thymic stromal lymphopoietin, we found that IL-25 was not essential for skin DC migration or hapten-specific T H cell differentiation in the sensitization phase of CHS. Unexpectedly, mast cell– and non–immune cell–derived IL-25 was important for hapten-specific T H 17 cell–mediated rather than T H 2 cell–mediated inflammation in the elicitation phase of CHS by enhancing T H 17-related, but not T H 2-related, cytokines in the skin. In particular, IL-1β produced by dermal DCs in response to IL-25 was crucial for hapten-specific T H 17 cell activation, contributing to induction of local inflammation in the elicitation phase of CHS. Conclusion Our results identify a novel IL-25 inflammatory pathway involved in induction of T H 17 cell–mediated, but not T H 2 cell–mediated, CHS. IL-25 neutralization can be a potential approach for treatment of CHS.