Introduction
Skin is a dynamic organ which creates epidermis over one’s lifetime through cell division and differentiation. Stratum corneum has been identified as a core tissue of the skin barrier that can withstand physical and chemical damages as well (Oh & Jang, 2015). The skin barrier function of the epidermis enables normal biochemical metabolisms, and protects skin from drying and external harmful factors (Chang & Lee, 2012).
Epidermal keratinocyte creates various proteins and lipids through the cell division and differentiation from epidermal stem cells on stratum basale, and finally forms stratum corneum via this phenomenon to rapidly change into corneocyte (Hong, 2011; Oh & Jang, 2015; Yoon et al., 2013).
Stratum corneum structure consists of corneocyte, cornified cell envelope, intercorneocyte lipid (lamellar membrane lipid) and corneodesmosome, and it serves as the skin barrier (Youm, 2013). When the differentiation process of epidermal keratinocyte is carried out abnormally, functional disorders of the skin barrier arise (Oh & Jang, 2015). The skin barrier can be divided into 4 types as physical, chemical, biochemical and immunological barrier (Jin & Lee, 2014), and stratum corneum has been reported as having an influence on simple barrier functions as well as the the structure and the functional roles of living cell layers such as epidermis and dermis (Jeong et al., 2009). Skin barrier research recently has been emerging as the most popular field of study in the dermatology and cosmetics industry due to its aesthetic importance (Kim & Jeong, 2012; Lee, 2014).
And to conclude, the epidermal keratinocytes form the stratum corneum via the proliferation, differentiation and a sort of apoptosis. These are finally goes through the desquamation process. Therefore, it is essential to understand the mechanism and factors that control these processes (Kim & Lee, 2008), and the main components of skin barrier are examined as follows.
Components of the skin barrier
1. Bricks and Mortar model
Stratum corneum consists of corneocytes that cross-linked with lipids and proteins (Park et al., 2001). Epidermal keratinocyte changes to corneocyte through proliferation and final differentiation, and it desquamates as a result of protease existing in the stratum corneum, a process that generates various proteins and lipids. The most typical model used to explain the structure and function of the stratum corneum is the two-compartment model, which was explained as a “Brick & Mortar” model by Elias (1996). This model explains stratum corneum consisting of protein (40%), lipid and moisture (20%) as the bricks and intercorneocyte lipid as the mortar, and corneodesmosome which is the protein structure connecting corneocytes, cornified envelope and cornified lipid envelope surrounding corneocytes are representative components of stratum corneum, which prevent fluids in the body from being lost and block the penetration of harmful substances from the outside (Kim & Jeong, 2012).
2. Lamellar bodies, profilaggrin/filaggrin
Lamellar bodies (LB) formed on Golgi apparatus include lipid components that will form intercorneocyte lipid, various lysosomal enzymes that provide the catalytic action for hydrolysis of corneodesmosome, lipids including phospholipids, sphingomyelin, glucosylceramide and cholesterol and enzymes including lipid hydrolase, lycosidase, protease and acid phosphatase, helping to form the barrier function (Hong, 2011). LB starts to appear from the top of the stratum spinosum and it exists most abundantly in the stratum granulosum, adhering to cell envelope on the boundary between stratum granulosum and stratum corneum and discharging lipids to intercellular space through extracellular secretion. ω-Hydroxyceramides are included inside LB of corneocyte lipid envelope (Im, 2014).
When epidermal keratinocyte reaches the stratum granulosum, it synthesizes keratohyalin granules which contain profilaggrin and loricrin. In normal skin, filaggrin exists inside keratohyalin granules in form of profilaggrin, which is a precursor and is hydrolyzed by proteolytic enzymes and becomes filaggrin through the dephosphorylation process. As the name suggests, a filament aggregating protein (filaggrin) acts as an adhesive to glue keratins together and it is also involved in binding of proteins composing cornified cell envelope such as involucrin and loricrin. Actually, its correlation in that the defect of filaggrin gene was observed from patients with atopic dermatitis and reduced ceramide on the lipid envelope of barrier has been reported, and transurocanic acid which is the final metabolite of this protein and some amino acids (arginine, glutamine and histidine) also act as natural moisturizing factor (NMF) which has the function of adjusting the pH of stratum corneum and protecting skin from UV rays and role of humectants (Kim, 2008; Kim & Jeong, 2012).
3. Lamellar membrane lipid, intercorneocyte lipid
In sensitive, dry and atopic skin, it is known that the function of lipid envelope which is the skin barrier is often damaged (Chang & Lee, 2012). Generally, skin lipids which act as barriers refer to intercorneocyte lipid and originate from LB. Intercorneocyte lipid is considered the mortar in the ‘Brick and Mortar model’ and it accounts for approximately 10% of the mass of stratum corneum (Im, 2014). Skin barrier lipid consists of ceramide, cholesterol and free fatty acids at a molecular ratio of 1:1:1, and the permeability barrier and antimicrobial barrier of stratum corneum coexist. Sphingolipids which are typical skin barrier lipids and sphingolipid metabolite sphingosine 1-phosphate also provide the antimicrobial action (Kim, 2008).
It is considered that a functional change of skin barrier in aged skin results from abnormality in important lipid components for forming the lamellar structure of stratum corneum and the function of skin barrier deteriorates accordingly (Park et al., 2001), and important elements (moisture content of stratum corneum, epidermis pH) for maintenance and the basic functions of skin barrier are damaged and lipid synthesis is reduced so that total lipid content of intercorneocyte lipid envelope decreases (Choi & Park, 2010). Intercorneocyte lipid forms lipid envelope in various layers called a lamellar structure, and in particular, the ceramide element is known to play an important role in the function of intercorneocyte lipid, and various moisturizers such as physiologic lipid mixture are being developed based on this premise (Choi, 2001; Jeong et al., 2009).
4. Cornified cell envelope (CE)
Two types of granules are formed inside epidermal keratinocyte on the stratum granulosum including keratohyalin filled with protein and lamellar bodies filled with lipid, and cornified protein envelope and cornified lipid envelope together are called cornified cell envelope (CE), which forms the boundary of corneocytes. In the beginning of the process of generating CE, envoplakin and involucrin adhere to the cell plasma membrane. Loricrin secreted from keratohyaline granule of the stratum granulosum is deposited on the desmosome of the cell envelope, and filaggrin aggregates keratin in the cell, forming macrofibril. The cornified lipid envelope is the lipid envelope generated when proteins forming the cornified envelope based on involucrin existing in corneocyte are connected to ω-hydroxyceramides among the lipids outside the corneocyte through covalent bonding. CE is an insoluble composite protein and lipid envelope (approximately 10 nm) and it has the structure of a protein envelope inside and a lipid envelope outside. As the protein envelope is differentiated and the calcium concentration inside the epidermal keratinocyte increases, the expression of envoplakin and periplakin occurs in the corneodesmosome and involucrin is located near the cell envelope. Involucrin is combined through cross-linkage between involucrins or involucrin, envoplaskin and periplakin by membrane-bound transglutaminase 1 (TGM1) and such desmosome surrounds along the inner surface of the cell envelope including corneodesmosome, forming a layer. In this process, loricrin, small proline rich proteins (SPRRs) and elafin are also mixed and combined with the protein envelope as well as keratin fibers so that the envelope protein is connected to the inside of the cell. Loricrin is combined with SPRRs by transglutaminase-3 more inside than involucrin, becoming a major component which accounts for 80% of the cornified cell envelope (Hong, 2011; Kalinin et al., 2001; Kim & Jeong, 2012).
5. Epidermal calcium gradient, cytokine
Calcium is an essential element for controlling the homeostasis of the skin barrier, and a change in the concentration of the calcium ion on the epidermis is known to be an important control factor for recovery after skin barrier damage. The decrease of the calcium concentration acts as a signal to secrete LB and synthesize lipids, and this supports the premise that calcium gradient plays an important role in forming the skin barrier. However, it is still not clear whether or not the development of a skin barrier is induced by a difference in calcium concentration in epidermis, or whether or not the skin barrier causes a difference in the calcium concentration in the epidermis (Kim, 2010; Ko, 2014). When the skin barrier is under damaged circumstance, cytokines, such as tumor necrosis factor (TNF) and interleukin (IL), especially IL1 and IL6, are secreted at first. However, if the barrier damage persists and these cytokines rise chronically, it may cause an adverse result such as inflammation or proliferation (Jin & Lee, 2014).
According to the skin dryness process, a “cytokine cascade” is formed due to changes in the moisture inflow, overall ion distribution and secretion of various cytokines such as IL1 on the stratum corneum during the epidermal damage process. Also, as DNA synthesis increases, abnormal corneocyte proliferation occurs, causing inflammation and the barrier restoration such as secretion of lamellar body or proliferation of biosynthesis of lipids also occurs due to epidermal barrier damage. Abnormal epidermal keratinocyte differentiation occurs due to cytokine cascade and scale occurs due to desquamation of damaged stratum corneum. This leads to a vicious circle of transepidermal water loss (TEWL) increase, decrease in moisture content of stratum corneum, loss of epidermis NMF and enzyme denaturation of stratum corneum, making skin dryness worse (Kim, 2007).
One controversial issue is the question of whether or not skin barrier damage is involved in increasing the sensitization of a child with atopic dermatitis to allergens. If skin barrier damage is involved in the sensitization to respiratory allergens, it can be said that skin barrier damage plays a key role in the process by which atopic dermatitis develops into asthma. An interesting point is the fact that IL4, IL13 and IL25 reduces keratinocyte's filaggrin synthesis, and this becomes important evidence for presenting the model that skin barrier damage induces an inflammatory response and the induced inflammatory response damages the skin barrier again (Cho, 2012).
6. Moisturizer
Stratum corneum is the most important structure for skin moisture, and the epidermal permeability barrier is closely related to water content since the movement of moisture inside and outside the skin is controlled through the stratum corneum and a moisturizing factor which can draw and contain moisture exists (Hong, 2014). Elements generally known to be related to moisture content on stratum corneum include intercorneocyte lipid envelope, natural moisturizing factor and glycerol on stratum corneum (Choi & Park, 2010).
When the barrier function of skin is damaged, the maintenance of homeostasis such as lipid secretion and synthesis occurs, and it is known that when an external ointment containing intercorneocyte lipid component is applied to skin with a damaged skin barrier function, the skin's barrier function is restored (Jeong et al., 2009).
The biggest benefit that cosmetic products can offer to the skin barrier function is the moisturizing effect. The skin barrier is the most influential part for cosmetic products (Nam et al., 2012). Recently, more attention has been focused on the restoration of the barrier function for the moisturizer, and physiologic lipid mixture can currently be considered as the most ideal moisturizer (Park, 2007a), and it reinforces the lipid barrier function to adjust moisture content of stratum corneum, and intercorneocyte lipid component fulfills this function (Chang et al., 2007). Physiologic lipid mixture is effective in restoring damaged skin barrier, and for moisturizer made of proper composition between ceramide, cholesterol and fatty acid that are physiological lipids of skin, it is absorbed into epidermal cells on epidermis underneath the barrier layer through skin barrier, forming multi-layer lipid envelope of LB and discharged as intercorneocyte lipid of skin barrier again.
The developmental direction of moisturizer is to find a substance which can normalize the lipid composition and metabolism on stratum corneum based on the biochemical knowledge on stratum corneum that has been accumulated through studies carried out thus far (Park et al., 2001).
Peroxisome proliferator activated receptor (PPAR) has been reported to provide the function to promote keratinocyte differentiation and maintain the homeostasis of skin barrier when it is activated in addition to a lipid metabolism control function, so the development of moisturizer containing components inducing biosynthesis of skin lipids such as intercorneocyte lipid on stratum corneum and PPAR activator is being carried out (Chang & Lee, 2012; Park, 2007a), while for various protedclastic enzymes such as serine protease and aspartic protease involved in the binding force and hydrolysis of capsid protein on stratum corneum, activation is promoted where proper pH conditions and moisture exist, and studies to apply antagonistic conditions to promote or restrain the activation of such protedclastic enzymes are also being carried out (Kim, 2008).
As the non-invasive evaluation of skin barrier function and moisturizing effect became possible, resulting in the development in the studies on skin barrier and the evaluation of moisturizing function of cosmetic products, but the status of skin barrier consisting of epidermal keratinocyte, various lipids and proteins systematically cannot be evaluated properly, sometimes histological or molecular biological evaluations may also be necessary in order to accurately evaluate the barrier function. The human trial is still being most widely used for evaluating the moisturizing function of cosmetic products, both in Korea and abroad (Hong, 2014).
Conclusion
In stratum corneum, corneocyte, considered as the 'bricks' in the 'Bricks and Mortar' model, is connected to specialized lipid and corneodesmosome, the 'mortar' (Kim, 2007), and corneodesmosome which is a protein structure connecting corneocytes, cornified protein envelope and cornified lipid envelope surrounding corneocytes are representative components that form stratum corneum (Kim et al., 2013). Protein components forming the skin barrier include keratin which accounts for 80-90% of the corneocyte components, profilaggrin/filaggrin involved in the cohesion of keratins after stratum granulosum, precursor protein forming CE (involucrin, envoplakin, desmoplakin, loricrin, keratolinin, SPRRs, cystein-rich protein, cystatin α), cadherin protein forming corneodesmosome, desmoplakin and plakoglobin (Kalinin et al., 2001).
Epidermal keratinocyte goes through the final differentiation process while moving to the upper layer due to the calcium ion concentration gradient (Kim & Jeong, 2012) and proper calcium regulation is very important for maintaining the skin barrier function (Kim, 2010). Also, various cytokines interact with each other on the skin, and dissonance between cytokines may cause pathologic conditions (Ko, 2014).
Skin moisturizing is closely related to the moisture content of the stratum corneum. A decrease in the moisture content of the stratum corneum causes skin dryness as well as abnormality in skin barrier function, so the maintenance of proper moisture in the stratum corneum is an essential condition for preventing moisture loss on intercorneocyte lipid (Kim et al., 2015; Kwon et al., 2013). A moisturizer helps metabolic activity in the stratum corneum to be carried out smoothly (Chang et al., 2007) and affects the skin barrier function with various mechanisms. Significantly, as studies have indicated that it has a positive effect on the differentiation protein of epidermal keratinocyte and lipid synthesizing enzyme (Kim & Jeong, 2012; Park, 2007b), it is expected that a new moisturizer which can restore lamella structure effectively can be useful in treating various skin diseases accompanying xerosis as a adjunctive therapy (Park et al., 2003).
For a correct understanding of the basic concept of skin barrier function and more advanced studies, studies should be carried out to classify various defense functions of permeability barrier and skin and identify the correlation between these functions (Youm, 2013). The ultimate objective of skin barrier research is the future development of cosmetic products including medicines and moisturizers based on the findings (Kim & Jeong, 2012).