Published online before print December 21, 2007

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(American Journal of Pathology. 2008;172:86-97.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070161

Acute Modulations in Permeability Barrier Function Regulate Epidermal Cornification

Role of Caspase-14 and the Protease-Activated Receptor Type 2

Marianne Demerjian^*, Jean-Pierre Hachem, Erwin Tschachler, Geertrui Denecker, Wim Declercq, Peter Vandenabeele, Theodora Mauro^*, Melanie Hupe^*, Debra Crumrine^*, Truus Roelandt, Evi Houben, Peter M. Elias^* and Kenneth R. Feingold^*

From the Dermatology and Medical (Metabolism) Services,^*Veterans Administration Medical Center and Departments of Dermatology and Medicine, University of California–San Francisco, San Francisco, California; Dienst Dermatologie,Academisch Ziekenhuis-Vrije Universiteit Brussel, Brussels, Belgium; the Department of Dermatology,University of Vienna Medical School, Vienna, Austria: and the Department for Molecular Biomedical Research,University of Gent, Gent, Belgium

Stratum corneum comprises corneocytes, derived from outer stratum granulosum during terminal differentiation, embedded in a lipid-enriched extracellular matrix, secreted from epidermal lamellar bodies. Permeability barrier insults stimulate rapid secretion of preformed lamellar bodies from the outer stratum granulosum, regulated through modulations in ionic gradients and serine protease (SP)/protease-activated receptor type 2 (PAR2) signaling. Because corneocytes are also required for barrier function, we hypothesized that corneocyte formation could also be regulated by barrier function. Barrier abrogation by two unrelated methods initiated a wave of cornification, assessed as TdT-mediated dUTP nick end-labeling-positive cells in stratum granulosum and newly cornified cells by electron microscopy. Because cornification was blocked by occlusion, corneocytes formed specifically in response to barrier, rather than injury or cell replacement, requirements. SP inhibitors and hyperacidification (which decreases SP activity) blocked cornification after barrier disruption. Similarly, cornification was delayed in PAR2^–/– mice. Although classical markers of apoptosis [poly(ADP-ribose)polymerase and caspase (Casp)-3] remained unchanged, barrier disruption activated Casp-14. Moreover, the pan-Casp inhibitor Z-VAD-FMK delayed cornification, and corneocytes were structurally aberrant in Casp14^–/– mice. Thus, permeability barrier requirements coordinately drive both the generation of the stratum corneum lipid-enriched extracellular matrix and the transformation of granular cells into corneocytes, in an SP- and Casp-14-dependent manner, signaled by PAR2.