Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing

Abstract

The epidermis is a stratified squamous epithelium in which keratinocytes progressively undergo terminal differentiation towards the skin surface leading to programmed cell death. In this respect we studied the role of caspases. Here, we show that caspase-14 synthesis in the skin is restricted to differentiating keratinocytes and that caspase-14 processing is associated with terminal epidermal differentiation. The proapoptotic executioner caspases-3, -6, and -7 are not activated during epidermal differentiation. Caspase-14 does not participate in apoptotic pathways elicited by treatment of differentiated keratinocytes with various death-inducing stimuli, in contrast to caspase-3. In addition, we show that non-cornifying oral keratinocyte epithelium does not express caspase-14 and that the parakeratotic regions of psoriatic skin lesions contain very low levels of caspase-14 as compared to normal stratum corneum. These observations strongly suggest that caspase-14 is involved in the keratinocyte terminal differentiation program leading to normal skin cornification, while the executioner caspases are not

Death penalty for keratinocytes: apoptosis versus cornification

“…Using mutant ROCKI or ROCK inhibitors, it was shown that ROCK activity is required to establish a higher-ordered architecture of the actin cytoskeleton during the initial steps of epidermal sheet formation. 25 Since active, processed caspase-3 is not detectable in normal newborn or adult skin, 26,27 it is unlikely that caspase-3 is involved in ROCKI activation during epidermal differentiation. These findings also indicate that ROCKI activity probably requires an apoptotic environment to induce membrane blebbing.…”

“…55 Although different caspases are expressed in the adult epidermis (caspase-1, -2, -3, -4, -6, -7, -8, -9, -11 and -14), 26,56 evidence that the proapoptotic caspases take part in normal skin formation is absent. Despite an early suggestion that caspase-3 is required for corneocyte formation, 57 several other data point out that apoptotic caspases are not activated during adult keratinocyte cornification.…”

“…First, other research groups showed that caspase-3 and other apoptotic caspases remain unprocessed in differentiating keratinocytes. 26 Secondly, the use of caspase inhibitors to examine the involvement of proapoptotic caspases in keratinocyte cornification indicates that (i) when applied at 25 mM in organotypic skin cocultures, zVAD-fmk can block caspase-3 processing in UVB-induced apoptosis, but had no effect on keratinocyte differentiation that could be identified using light microscopy (Lippens S and Declercq W, unpublished data). However, application of broad-range caspase inhibitors at concentrations 4100 mM resulted in inhibition of keratinocyte cornification.…”

“…27 Importantly, one member of the caspase family, the nonapoptotic caspase-14, seems to be expressed and processed in association with keratinocyte differentiation. 26,63 The expression of caspase-14 is highly restricted to the skin and some other epithelial layers such as the choroid plexus, the retinal pigment epithelium and Hassall's bodies. 64 In the skin, caspase-14 expression occurs in the differentiating suprabasal cells (Figure 3).…”

Caspases on the brain

“…In contrast, the phenotypes of other knockouts are very severe, are evidently antiapoptotic, and vary from early embryonic lethality (caspase 8), to perinatal lethality (caspases 3 and 9; Kuida et al, 1996Kuida et al, , 1998Varfolomeev et al, 1998), to relatively mild effects with defects in the process of normal oocyte ablation (caspase 2; Morita et al, 2001). Currently, caspase 14 may be the odd man out, being involved in keratinocyte differentiation (Eckhart et al, 2000;Lippens et al, 2000). Humans and mice each contain 11 caspases, and most (if not all) of these are found in the brain, either in neurons or (especially in the case of the inflammatory caspases) in glia.…”