Functional caspase-1 is required for langerhans cell migration and optimalcontact sensitization in mice

Langerhans cell (LC) migration from epidermis to draining lymph node is a c ritical first step in cutaneous immune responses. Both TNF-alpha and IL-1 b eta are important signals governing this process, but the potential regulat ory role of LL-l alpha processing by caspase-1 is unknown, In wild-type (WT ) mice, application of the contact allergens 2,4-dinitrofluorobenzine and o xazolone lead to a marked reduction in epidermal LC numbers, but in caspase -1-deficient mice this reduction was not observed. Moreover, although intra dermal injection of TNF-alpha (50 ng) induced epidermal LC migration in WT mice, this cytokine failed to induce LC migration in caspase-1-deficient mi ce. Intradermal IL-1 beta) (50 ng) caused a similar reduction in epidermal LC numbers in both WT and caspase-1-deficient mice, indicating that, given an appropriate signal, caspase-1-deficient epidermal LC are capable of migr ation. Contact hypersensitivity to both 2,4-dinitrofluorobenzine and oxazol one was inhibited in caspase-1-deficient mice, indicating a functional cons equence of the LC migration defect. In organ culture the caspase-1 inhibito r Ac-YVAD-cmk, but not control peptide, potently inhibited the epidermal LC migration that occurs in this system, and reduced spontaneous migration of LC was observed in skin derived from caspase-1-deficient mice. Moreover, A c-YVAD-cmk applied to BALB/c mouse skin before application of contact sensi tizers inhibited LC migration and contact hypersensitivity in vivo. Taken t ogether, these data indicate that Caspase-1 may play a central role in the regulation of LC migration and suggest that the activity of this enzyme is amenable to control by specific inhibitors both in vivo and in vitro.