Apoptotic pathways in the epidermis

Programmed cell death of epidermal keratinocytes occurs in two forms – classical apoptosis after irreparable cellular injuries and during terminal keratinocyte differentiation – leading to stratum corneum formation. Whereas the former is indistinguishable from apoptosis in other tissues and leads to cellular disintegration, the latter results in establishment of ‘indestructible’ cellular ghosts. Although there are several similarities between these two forms of programmed cell death such as the loss of the nucleus and cellular organelles, the persistence of dead keratinocytes as corneocytes represents a major difference. As to the molecular events which drive both processes, many known factors of the pro- and anti-apoptotic machinery are expressed by keratinocytes and appear to become active after UV irradiation or other damaging insults but not in the last phase of keratinocyte differentiation. By contrast, distinct members of the pro-apoptotic enzyme families such as caspases and DNases are expressed almost exclusively in epidermal keratinocytes. Most notably, caspase-14 and DNAse1L2 are upregulated and activated in a differentiation-associated manner. This suggests that certain elements of the molecular apoptotic machinery have adapted to specific roles in terminal differentiation-associated cell death in the epidermis. Allombert-Blaise C, Tamiji S, Mortier L, et al. Terminal differentiation of human epidermal keratinocytes involves mitochondria- and caspase-dependent cell death pathway. Cell Death Differ 2003: 10: 850-852. This article evidenced that the differentiation process in epidermal keratinocytes uses mitochondrial-dependent death machinery and suggested that differentiation is regulated by a balance of prepression and activation between proliferation and apoptosis. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 2005: 6: 328-340. This article is an excellent overview on the insights into the molecular mechanisms and the physiological endpoints of cornification and the current understanding of the pathological defects of this form of programmed cell death. Chang CH, Yu M, Wu P, et al. Sculpting skin appendages out of epidermal layers via temporally and spatially regulated apoptotic events. J Invest Dermatol 2004: 122 (6): 1348-1355. This article examines apoptosis in the morphogenesis of skin appendages and shows how adding and removing cell masses in temporally and spatially specific ways are coordinated to sculpt skin appendages from epidermal layers. Chaturvedi V, Qin JZ, Denning MF, Choubey D, Diaz MO, Nickoloff BJ. Apoptosis in proliferating, senescent, and immortalized keratinocytes. J Biol Chem 1999: 274: 23358-23367. The authors demonstrate that growth arrest, confluency, and senescence of keratinocytes are associated with resistance to classical apoptosis and that differentiation of keratinocytes is no prerequisite for conventional apoptosis induction. Eckhart L, Declercq W, Ban J, et al. Terminal differentiation of human keratinocytes and stratum corneum formation is associated with caspase-14 activation. J Invest Dermatol 2000: 115: 1148-1151. Demonstration that expression and activation of an epidermis-specific caspase correlates with terminal keratinocyte differentiation in vitro. Gandarillas A, Goldsmith LA, Gschmeissner S, Leigh IM, Watt FM. Evidence that apoptosis and terminal differentiation of epidermal keratinocytes are distinct processes. Exp Dermatol 1999: 8: 71-79. Comparison of normal epidermis and epidermis from skin diseases with disturbed differentiation with no evidence of increased apoptosis in the latter despite a higher proportion of TUNEL-positive cells (suggestive that TUNEL is not a specific marker of apoptosis in keratinocytes). Together with in vitro data conclusion that in vivo and in culture keratinocyte terminal differentiation and apoptosis are distinct cellular events subject to different stimuli. Kuechle MK, Presland RB, Lewis SP, Fleckman P, Dale BA. Inducible expression of filaggrin increases keratinocyte susceptibility to apoptotic cell death. Cell Death Differ 2000: 7: 566-573 The authors generated keratinocyte cell lines expressing mature human filaggrin under an inducible promoter system and found that these cell lines exhibited increased sensitivity to multiple apoptotic stimuli. They conclude that filaggrin, which is expressed at a level of the epidermis where keratinocytes are in transition between the nucleated granular and the anucleate cornified layers, aids in the terminal differentiation process by facilitating apoptotic machinery. Pena JC, Fuchs E, Thompson CB. Bcl-x expression influences keratinocyte cell survival but not terminal differentiation. Cell Growth Differ 1997: 8: 619-629. Overexpression of bcl-xL or bcl-xS under the control of the K14 promoter did not compromise the maturation process and cellularity of the epidermis but dramatically increase resistance (bcl-xL) or sensitivity (bcl-xS) to irradiation. Their findings demonstrate that the terminal differentiation program of keratinocyte is not altered by the overexpression of anti-apoptotic proteins. Takahashi H, Aoki N, Nakamura S, Asano K, Ishida-Yamamoto A, Iizuka H. Cornified cell envelope formation is distinct from apoptosis in epidermal keratinocytes. J Dermatol Sci 2000: 23: 161-169. The authors analyzed the effects of the calcium ionophore A23187 and UV on keratinocytes and demonstrated that although both treatments lead to the cell death of keratinocyte, they followed two distinct pathways (i.e. conventional apoptosis and formation of cornified envelope respectively) and concluded that CE formation is distinct from apoptosis in epidermal keratinocytes. Weil M, Raff MC, Braga VM. Caspase activation in the terminal differentiation of human epidermal keratinocytes. Curr Biol 1999: 9: 361-364. The authors report that pro-apoptotic caspases are activated during normal human keratinocyte differentiation and that this activation is apparently required for the normal loss of the nucleus. Wrone-Smith T, Johnson T, Nelson B, et al. Discordant expression of Bcl-x and Bcl-2 by keratinocytes in vitro and psoriatic keratinocytes in vivo. Am J Pathol 1995: 146: 1079-1088. The authors analyzed the expression of pro- and anti-apoptotic regulators in keratinocytes in vitro and in vivo and suggested that the overexpression of Bcl-x in psoriasis may contribute to the longevity of keratinocytes by blocking the normal apoptotic process involved in the terminal differentiation.