Cornification of the Skin: A Non‐apoptotic Cell Death Mechanism

Abstract

The most important function of the epidermis is to form a barrier against the environment by means of several layers of terminally differentiated, dead keratinocytes, the cornified envelope (CE). CEs consist of keratins enclosed within an insoluble amalgam of proteins and lipids. Transglutaminase enzymes catalyse the formation of characteristic crosslinks between structural proteins to form the protein part of the CE. Another form of cell death, that is, apoptosis, which has a completely different molecular mechanism and physiological significance, also occurs in the skin. Defects of apoptosis are related to the development of cancer, whereas CE abnormalities are associated with barrier abnormalities and ichthyosis. Key concepts: Keratinocyte apoptosis (occurring in basal layer) is an active and rapid, energy‐dependent, gene‐directed biochemical pathway of defensive cell death that does not require de novo protein synthesis and preserves plasma membrane. Cornification, the keratinocyte differentiation programme (occurring in upper layer), is a slow, coordinated process in space and time, which allows the formation of a layer of dead cells (corneocytes) to create a physical barrier for the skin. The stratum corneum is composed of tightly attached corneocytes with mostly keratin intermediate filaments (KIFs) embedded into a filaggrin matrix. The structural proteins of the CE, including involucrin, loricrin, trichohyalin and the class of small proline‐rich proteins (SPRs), constitute about 7–10% of the mass of the epidermis. These structural proteins together with lipids (ceramides) form the complete barrier. Transglutaminase are Ca 2+ ‐dependent enzymes that catalyse the formation of N ε ‐(γ‐glutamyl)lysine bonds between CE structural proteins to confer the characteristic resistance and insolubility to the skin. The junctions responsible for intercellular adhesion and for cohesion of the stratum corneum of the epidermis are of two types: (1) the adherence junctions (connecting the actin cytoskeleton of neighbouring cells) and (2) desmosomes (connecting the keratin filament cytoskeleton of adjacent cells). Proteases are involved in at least three processes in skin differentiation. First, certain cornified envelope precursors require proteolytic processing before cornified envelope formation occurs. Second, the loss of nuclei and mitochondria requires proteolytic processing. Third, desquamation requires proteolysis of the corneodesmosomes.

The development of the mammalian outer and middle ear

“…), suggesting this developmental step could involve the initiation of cornification in this epithelium: as cornification involves a non‐apoptotic cell death mechanism that is TUNEL‐negative (Candi et al. ).…”

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“…Epidermal layers in the thick skin of the palms of the hands distinguished by cell types. The process of terminal differentiation occurs as cells move up to the outermost layer of skin, generating an outer layer consisting of flattened keratinocytes lacking nuclei (corneocytes) made mostly of keratin filaments joined tightly together in a lipid-and proteindense, highly cross-linked matrix[121].…”

IgE Autoreactivity in Atopic Dermatitis: Paving the Road for Autoimmune Diseases?

“…Skin barrier function emerges from the controlled process of keratinocyte death by cornification. Injury, infection, and inflammation promote keratinocytes proliferation and differentiation and disrupt this tightly regulated process, which leads to skin barrier dysfunction [ 10 , 11 ]. Injuring the keratinocytes’ layer directly with the topical application of chemicals such as calcipotriol, or mechanically by tape stripping (modelling scratching) induces AD-like symptoms in an antigen-independent manner.…”