Corneocytes

Corneocytes are formed by the terminal differentiation of the keratinocytes from the granular layer of the epidermis. The epidermis contains 70% water as do most tissues, yet the SC contains only 15% water. Alongside this change in water content the keratinocyte nuclei and virtually all the subcellular organelles begin to disappear in the granular cell layer leaving a proteinaceous core containing keratins, other structural proteins, free amino acids, and amino acid derivatives, and melanin particles that persist throughout the SC. From an oval or polyhedral shape of the viable cells in the spinous layers, the keratinocyte starts to flatten off in the granular cell layer and then assumes a spindle shape and finally becomes a flat corneocyte. The corneocyte itself develops a tough chemically resistant protein band at the periphery of the cell, called cornified cell envelope, formed from cross‐linked cytoskeletal proteins [3].

Water evaporation barrier (epidermal permeability barrier)

Perhaps the most studied and the most important function of SC is the formation of the epidermal permeability barrier [1, 4, 9]. SC limits the transcutaneous movement of water and electrolytes, a function that is essential for terrestrial survival. Lipids, particularly ceramides, cholesterol, and FFAs, together form lamellar membranes in the extracellular spaces of the SC that limit the loss of water and electrolytes. Corneocytes are embedded in this lipid‐enriched matrix, and the CE, which surrounds corneocytes, provides a scaffold necessary for the organization of the lamellar membranes. Extensive research, mainly by Peter Elias’ group has elucidated the structure, properties, and the regulation of the skin barrier by integrated mechanisms [5, 10, 11]. Barrier disruption triggers a cascade of biochemical processes leading to rapid repair of the epidermal barrier. These steps include increased keratinocyte proliferation and differentiation, increased production of corneocytes and production, processing and secretion of barrier lipids, ultimately leading to the repair of the epidermal permeability barrier. These events are described in more detail in the barrier homeostasis section below. A list of the different functions of human epidermis is shown in Table 1.2.

Mechanical barrier

CE provides mechanical strength and rigidity to the epidermis, thereby protecting the host from injury. Specialized protein precursors and their modified amino acid cross‐links provide the mechanical strength to the SC. One such protein, trichohyalin is a multifunctional cross‐bridging protein that forms intra and inter protein cross‐links between cell envelope structure and cytoplasmic keratin filament network [12]. Special enzymes called transglutaminases, some present exclusively in the epidermis (transglutaminase 3), catalyze this cross‐linking reaction. In addition, adjacent corneocytes are linked by corneodesmosomes, and many of the lipids of the SC barrier are also chemically cross‐linked to the CE. All these chemical links provide the mechanical strength and rigidity to the SC.

Antimicrobial barrier and immune protection

The epidermal barrier acts as a physical barrier to pathogenic organisms that attempt to penetrate the skin from the outside environment. Secretions such as sebum and sweat and their acid pH provide antimicrobial properties to skin. Microflora that normally inhabit human skin can contribute to the barrier defenses by competing for nutrients and niches that more pathogenic organisms require, by expressing antimicrobial molecules that kill or inhibit the growth of pathogenic microbes and by modulating the inflammatory response [13]. Desquamation that causes the outward movement of corneocytes and their sloughing off at the surface also serves as a built‐in mechanism inhibiting pathogens from colonizing the skin. Innate immune function of keratinocytes and other immune cells of the epidermis such as Langerhans cells and phagocytes provide additional immune protection in skin. Epidermis also generates a spectrum of antimicrobial lipids, peptides, nucleic acids, proteases, and chemical signals that together forms the antimicrobial barrier (Table 1.3). The antimicrobial peptides are comprised of highly conserved small cysteine‐rich cationic proteins that are expressed in large amounts in skin. They contain common secondary structures that vary from α helical to β sheets, and their unifying characteristic is the ability to kill microbes or inhibit them from growing. Pathways that generate and regulate the antimicrobial barrier of the skin are closely tied to pathways that modulate the permeability barrier function. Expression of endogenous AMPs coincides with the presence of a number of epidermal structural components that may become part of the permeability barrier. For instance, murine cathelin‐related antimicrobial peptide CRAMP and mBD‐3 are essential for permeability barrier homeostasis. In addition, acute and chronic skin barrier disruption lead to increased expression of murine β‐defensins (mBDs)‐1, ‐3, and ‐14, and this increase in expression is diminished when the barrier is artificially restored [13].

NMF and skin hydration/moisturization

NMF is a collection of water‐soluble compounds that are found in the SC (Table 1.4). These compounds compose approximately 20–30% of the dry weight of the corneocyte. Many of the components of the NMF are derived from the hydrolysis of filaggrin, a histidine‐, and glutamine‐rich basic protein of the keratohyalin granule. SC hydration level controls the protease that hydrolyzes filaggrin and histidase that converts histidine to urocanic acid. As NMF is water soluble and can easily be washed away from SC, the lipid layer surrounding the corneocyte helps seal the corneocyte to prevent loss of NMF.

In addition to preventing water loss from the organism, SC also acts to provide hydration and moisturization to skin. NMF components absorb and hold water allowing the outermost layers of the SC to stay hydrated despite exposure to the harsh external environment. Glycerol, a major component of the NMF, is an important humectant present in skin that contributes skin hydration. Glycerol is produced locally within SC by the hydrolysis of triglycerides by lipases but also taken up into the epidermis from the circulation by specific receptors present in the epidermis called Aquaporins [14]. Other humectants in the NMF include urea, sodium, and potassium lactates and PCA [9].