[Academic Presentation] Recent Advances in Research on the Epidermal Permeability Barrier and Its Relationship to Other Barrier Functions

The epidermal permeability barrier serves as a bridge between the internal milieu of the organism and the external environment. It is primarily composed of the stratum corneum, a multilayered lamellar structure formed by 5 to 15 stacked layers of cornified cells—whose nuclei and organelles have been lost—embedded within a continuous matrix of hydrophobic intercellular lipids. In the 1970s, Professor Peter Elias aptly likened this structural arrangement to a “brick‑and‑mortar” architecture: the cornified cells function as the “bricks,” generated through the continuous proliferation and differentiation of keratinocytes as they migrate from the basal layer toward the stratum corneum, while the intercellular lipids constitute the “mortar.” These lipids are predominantly synthesized in the granular layer within lamellar bodies and released via exocytosis into the extracellular space between keratinocytes; they consist of ceramides (approximately 50%), free fatty acids (10%–20%), and cholesterol (about 25%). Concurrently, filaggrin, loricrin, involucrin, and other proteins form an extensive cross‑linked network on the plasma membrane of keratinocytes, creating a cornified envelope that interdigitates with the intercellular lipids. This composite structure confers resistance to proteolytic degradation, acid–base stress, and external insults, thereby enhancing the stability of the epidermal permeability barrier. Consequently, the intact stratum corneum, with its cornified cells embedded within an intercellular matrix, plays a pivotal role in maintaining skin barrier function.

Maintaining a robust skin barrier and preventing transepidermal water loss are key functions of the stratum corneum, playing a critical role in skin health. Under normal conditions, the stratum corneum loses 2–5 g/h·cm² of water through the epidermis; when the stratum corneum is compromised, transepidermal water loss (TEWL) increases. If the entire stratum corneum is stripped away, transcutaneous water loss can rise by as much as 30-fold. When ambient humidity drops below freezing, water evaporates from the skin surface until a new equilibrium is established between the stratum corneum and the surrounding environment. As temperature declines, the moisture content of the stratum corneum also decreases, making the skin more prone to cracking in cold, dry conditions. If the cell membrane is damaged—due to friction, excessive use of detergents, or lipid‑soluble agents—water can be lost from cells even under favorable environmental humidity. Furthermore, with a weakened skin barrier, water diffusion at sites of skin injury accelerates, leading to increased dryness and triggering a cascade of inflammatory and immune responses that can exacerbate various dermatological conditions, such as psoriasis, eczema, and atopic dermatitis.

The epidermal permeability barrier is closely linked to other skin barrier functions. When the epidermal permeability barrier is compromised, it can lead to cutaneous immune dysregulation and microbial infections; conversely, dysfunction of other skin barrier components can further exacerbate impairment of the epidermal permeability barrier.

Nearly a century ago, Schade first coined the term “acid mantle” to describe the inherent acidity of the stratum corneum, thereby drawing the attention of many scientists to the importance of pH changes on the skin’s surface. Over the past decade or so, research has shown that the pH of the skin’s surface… The pH value can influence the homeostasis of the epidermal permeability barrier, the integrity and cohesion of the stratum corneum, and the skin’s antimicrobial defense mechanisms. Normal skin is slightly acidic, with a pH ranging from 5.5 to 7.0, and can drop as low as 4.0. Only when the skin maintains a normal pH—i.e., remains in the mildly acidic range—can it achieve optimal resistance to external aggressors.

Recent studies have shown that changes in the skin’s surface pH are also crucial for maintaining the normal function of the epidermal permeability barrier. Maum et al. disrupted the epidermal barrier in hairless mice using acetone and tape, demonstrating that under acidic conditions, the epidermal permeability barrier exhibits a stronger capacity for repair than under neutral conditions. Experiments by Stenzaly et al. revealed that blocking or knocking out phospholipase A2 or the sodium‑ion exchanger—both of which contribute to stratum corneum acidification—can compromise the homeostasis of the epidermal permeability barrier and the integrity of the stratum corneum. Furthermore, Hachem et al., employing a hairless mouse model, found that when the skin’s surface pH decreases, the epidermal permeability barrier can be restored even before any changes occur in the basal layer of the epidermis.

The reason why the skin’s surface pH affects the function of the epidermal permeability barrier may be related to the fact that several key enzymes involved in the synthesis of lipid components within this barrier are pH‑dependent. For example, two crucial enzymes responsible for synthesizing ceramides—the major lipid component of intercellular cement in the stratum corneum—are acid phosphatase and β‑glucocerebrosidase, which require pH values of 4.5 and …, respectively. 5. 6. Experiments have shown that when the pH increases from 5.5 to 7.4, the activity of β-glucocerebrosidase can decrease by a factor of ten. Furthermore, both the secretion of lipids by lamellar bodies and the formation of the lamellar structure in the stratum corneum require an acidic environment.

Because an acidic environment can promote the repair of the epidermal permeability barrier, some researchers have applied acidic agents in the treatment of skin diseases associated with impaired epidermal permeability barriers, achieving favorable therapeutic outcomes. Hachem et al. demonstrated that polyhydroxy acids can improve the function of the epidermal permeability barrier in neonates and elderly individuals. Chinese researchers led by Lai Wei found that the pH at lesional sites in patients with atopic dermatitis is significantly higher than that of normal skin, with a reduced capacity to buffer acid–base changes. Following topical application of a 5% L‑lactic acid gel to the lesions, they observed that the pH at the lesion site… The value decreased, while the TEWL was reduced and the epidermal water content increased compared with the untreated area. This further demonstrates that, in clinical practice, topical application of acidic agents can repair the epidermal permeability barrier, thereby achieving therapeutic effects for certain skin diseases.

The epidermal permeability barrier also modulates cutaneous immune responses. To assess the impact of a compromised epidermal permeability barrier on skin immunity, Godefroy et al. disrupted the barrier in BALB/c mice using repeated tape‑stripping and then applied antigens—diphtheria toxin–non‑toxic mutant CRM197 and cholera toxin—to the skin, with additional applications at 21 and 42 days to amplify the immune response. The results showed that antigen‑specific immune responses were detectable in mice with a damaged epidermal barrier, whereas such responses were absent in normal mice, indicating that various exogenous antigens can penetrate the body through a compromised epidermal barrier, triggering immune and inflammatory reactions. Pan et al. demonstrated that free fatty acids, fatty acid‑binding protein 4, and fatty acid‑binding protein 5 within the extracellular matrix play critical roles in maintaining the normal physiological functions of memory T lymphocytes. Serine palmitoyltransferase is a key enzyme in the synthesis of ceramides, the major lipid component of intercellular cement in the stratum corneum; Nakajima et al. used mice lacking serine palmitoyltransferase to examine how reduced ceramide synthesis affects cutaneous immune responses. After two weeks, they observed increased Langerhans cell activity and enhanced migration to lymph nodes, along with an elevation in γδ T lymphocytes, accompanied by hyperkeratosis, loss of the spinous and granular layers, and inflammatory cell infiltration—features reminiscent of psoriasiform skin lesions. These findings underscore the pivotal role of intercellular lipids, which constitute the “mortar” of the epidermal permeability barrier, in orchestrating cutaneous immune responses.

Conversely, skin inflammation and immune responses can also impair the epidermal permeability barrier. In lesional skin of patients with atopic dermatitis, IL‑22 is present. Expression was markedly increased. Lou et al., using a specialized inducible transgenic skin model, demonstrated that IL‑2, by activating the GRP signaling pathway, not only elicits an immune response predominantly characterized by Th2 responses but also leads to disruption of the epidermal permeability barrier.

The skin serves as the body’s first line of defense against the invasion and proliferation of pathogenic microorganisms. Numerous microorganisms inhabit the skin; some, through long-term mutual adaptation, can persist on the skin for extended periods and are referred to as the skin’s normal microbiota, or simply the skin’s normal flora. These microorganisms maintain close interactions with one another and with their host, influencing each other and together constituting the skin’s microecology. Consequently, the epidermal permeability barrier and the skin’s microecology form an integrated system in which alterations in either component may contribute to the development of disease.

Van Drongelen et al. demonstrated that silencing filaggrin, a major component of the cornified envelope in keratinocytes of the stratum corneum, significantly enhances Staphylococcus aureus colonization in the epidermis, while also increasing IL‑8 expression, thereby triggering cutaneous inflammatory responses and infection. Jinnestüll et al., through a comparative study examining the correlation between alterations in the epidermal permeability barrier and bacterial colonization in 30 adult patients with atopic dermatitis, found that patients with positive staining for S. aureus, Malassezia, and Candida at lesional sites exhibited greater transepidermal water loss than those with negative staining for these microorganisms. These findings suggest that disruption of the epidermal permeability barrier promotes bacterial colonization, and extensive microbial colonization can facilitate the translocation of microbial antigens across the compromised barrier into the skin, ultimately precipitating IgE‑mediated allergic reactions.

Meanwhile, the skin serves as the body’s first line of defense against the invasion and proliferation of pathogenic microorganisms. In addition to the epidermal permeability barrier and the slightly acidic skin environment, this defensive role is further supported by the body’s innate defense mechanisms—namely, antimicrobial peptides. These small peptides are abundantly expressed in the skin, primarily synthesized in the deeper layers of the epidermis and transported to the stratum corneum, where they play a critical role in the initial defense against potential pathogens. Currently, the major antimicrobial peptides found in human skin belong to the defensin and cathelicidin families. Aberg et al. demonstrated that, following disruption of the epidermal permeability barrier for just one hour, the epidermis… The expression of antimicrobial peptide proteins and their mRNAs is markedly upregulated, with elevated levels of cathelicidin (LL‑37) mRNA and β‑defensins as well. Clausen et al. likewise demonstrated a correlation between the epidermal microbiome and the epidermal permeability barrier: by measuring β‑defensins, transepidermal water loss (TEWL), and lesion scores in the stratum corneum of lesional and non‑lesional skin from 25 patients with atopic dermatitis, as well as in 11 healthy controls, they found that β‑defensin levels were significantly higher in lesional than in non‑lesional skin and in the healthy control group, accompanied by increased TEWL and higher lesion scores. Czarnowicki et al., applying petroleum jelly to the skin surface of patients with atopic dermatitis, observed enhanced expression of filaggrin and loricrin, along with increased expression of antimicrobial peptides. These studies collectively indicate that disruption of the epidermal permeability barrier can perturb the cutaneous microbial balance and play a critical role in maintaining the skin’s innate defense functions.

In summary, the epidermal permeability barrier plays a crucial regulatory role in numerous biological functions of the skin and interacts with other skin… Barrier functions—such as the immune barrier, the acid mantle, and the skin microbiome—form an integrated defensive system. When one of these functions is disrupted, it can impair others, leading to the development of skin diseases. Consequently, in the clinical management of dermatologic conditions, treatment should not be limited to anti‑immune or anti‑inflammatory strategies; it must also address the repair of the compromised skin barrier, the regulation of the skin’s acidic surface environment, and the maintenance of microbial homeostasis. For example, studies have demonstrated that in atopic dermatitis, transepidermal water loss (TEWL) is elevated, accompanied by inflammatory responses and bacterial colonization, suggesting that this condition involves not only disruption of the epidermal permeability barrier but also impairment of the immune and microbial barriers. Therefore, clinical management requires not only anti‑inflammatory therapy but also restoration of the epidermal barrier and antimicrobial intervention.