IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL-1β by keratinocytes via the ROS-NLRP3-caspase-1 pathway

Background: The pathogenesis of inflammatory skin disease involves the release of cytokines from keratinocytes, and one of these, IL-1 beta, has been previously implicated in inflammatory skin disease. T(h)17 cells, a subset of T-h cells involved in autoimmunity and inflammation, possess IL-1 beta receptors and secrete cytokines such as IL-17 and IL-22 in response to IL-1 beta stimulation. A mutation in the inflammasome protein NLRP3 (NACHT, LRR and PYD domains-containing protein 3) causes excess production of IL-1 beta, resulting in an augmentation of T(h)17-dominant pathology. Methods: To determine the feedback effect, if any, of IL-17 and/or IL-22 on the secretion of IL-1 beta from keratinocytes, we stimulated the human keratinocyte cell line HaCaT, as well as caspase-1-deficient mice, with IL-17 or IL-22. Results: We found that treatment with IL-17 and IL-22 causes an increase in IL-1 beta via the activation of NLRP3 by a process that involves the generation of reactive oxygen species. Moreover, skin inflammation induced by IL-17 and IL-22 was lower in caspase-1 knockout (KO) mice relative to that induced by IL-1 beta treatment. Additionally, skin inflammation induced by the drug imiquimod was lower in caspase-1 KO mice than in wild-type mice. Conclusion: These results indicate that cytokines from T(h)17 cells may potentiate IL-1 beta-mediated skin inflammation and result in phenotypic alterations of keratinocytes via a feedback mechanism.