Dynamic expression of epidermal caspase-8 simulates a wound healing response

Tissue homeostasis and regeneration are regulated by an intricate balance of seemingly competing processes - proliferation vs. differentiation and cell death vs. survival1. Here we demonstrate that the loss of epidermal caspase-8, an important mediator of apoptosis2, recapitulates multiple phases of a wound healing response. The epidermal hyperplasia in the caspase-8 null skin is the culmination of signals exchanged between epithelial, mesenchymal, and leukocytic cells. This reciprocal interaction is initiated by the paracrine signaling of interleukin-1α (IL-1α) which activates both skin stem cell proliferation and cutaneous inflammation. The non-canonical secretion of IL-1α is induced by a p38 MAPK mediated upregulation of NALP3 leading to inflammasome assembly and caspase-1 activation. Interestingly, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocyte in the stratified epidermis by IL1α-dependent NFκB signaling. Altogether our findings illustrate how the loss of caspase-8 can have an impact beyond programmed cell death to affect the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.