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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 versus differentiation, and cell death versus survival1. Here we demonstrate that the loss of epidermal caspase 8, an important mediator of apoptosis2, recapitulates several phases of a wound healing response in the mouse. The epidermal hyperplasia in the caspase 8 null skin is the culmination of signals exchanged between epidermal keratinocytes, dermal fibroblasts and leukocytic cells. This reciprocal interaction is initiated by the paracrine signalling of interleukin 1α (IL1α), which activates both skin stem cell proliferation and cutaneous inflammation. The non-canonical secretion of IL1α is induced by a p38-MAPK-mediated upregulation of NALP3 (also known as NLRP3), leading to inflammasome assembly and caspase 1 activation. Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1α-dependent NFκB signalling. Altogether, our findings illustrate how the loss of caspase 8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.

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Figure 1: Effect of caspase 8 downregulation in the epidermis.
Figure 2: Characterization of the inflammatory response in the caspase 8 knockout skin.
Figure 3: Control of keratinocyte proliferation through epithelial–mesenchymal interactions.
Figure 4: Regulation of IL1α secretion.


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We thank S. Hedrick, W. Havran, B. Yu, D. Witherden, A. Hoffmann, D. Stachura and members of the Jamora laboratory for providing reagents and helpful discussions. This work was supported by grants from the National Institutes of Health (NIAMS grant number 5R01AR053185-03) and the American Skin Association, and a Career Award from the Dermatology Foundation.

Author Contributions P.L., D.L., C.C., S.C. and C.J. performed the experiments; I.C. engineered the caspase 8 floxed mice; P.L. and C.J. designed the experiments; P.L., D.L. and C.J. wrote the manuscript.

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Correspondence to Colin Jamora.

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Lee, P., Lee, DJ., Chan, C. et al. Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 458, 519–523 (2009).

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