Deficiency of inflammatory caspases attenuates IL-33–mediated dermatitis

Interleukin-33 (IL-33) is a nuclear alarmin expressed in epidermal keratinocytes and plays an important role in atopic dermatitis. Environmental stimulation induces extracellular release of IL-33 from the skin. The molecular mechanisms regulating IL-33 release in vivo are not well understood. Previous studies using non-cutaneous tissues or in vitro systems have suggested that IL-33 release is independent of caspase-1. In this study, we examined the role of caspase-1 in IL-33 release from keratinocytes in vivo . Caspase-1 was detected in the nuclei of murine epidermal keratinocytes. After topical stimulation with the hapten 2,4-dinitrofluorobenzene (DNFB), nuclear IL-33 staining in keratinocytes was rapidly lost in wild-type mice. This change was markedly reduced in caspase-1/11–deficient mice. Genetic deletion of caspase-1/11 reduced IL-33–mediated skin inflammation in mice overexpressing IL-33 in keratinocytes, and reduced expression of type 2 cytokines was also observed in the skin. These findings suggest that caspase-1 may play a role in pathogenic IL-33 release in the skin and may control alarmin activity differently across tissues.