Hyaluronic acid (HA), or hyaluronan, is a key component of the extracellular matrix (ECM) in vertebrates. In a 70 kg human body, there is approximately 15 g of HA, with up to 50% of the total concentrated in the skin (Fraser J.R. et al., 1997). While primary attention is traditionally given to HA in the dermis, where its concentration is highest, a significant amount of this substance is located in the intercellular spaces of the living epidermal layers—the stratum basale and stratum spinosum (Tammi R. et al., 1988). Here, HA not only plays a structural role but also actively participates in the formation of the epidermal barrier and in the regulation of vital keratinocyte functions (Evrard C. et al., 2021).

The Role of Hyaluronic Acid in the Epidermis

In a healthy epidermis, HA fills the narrow intercellular spaces (approximately 15–20 nm wide) between keratinocytes. Due to its high hydrophilicity, it can hold a large volume of water, imparting viscoelastic properties to the tissue and creating an environment favorable for the diffusion of nutrients, growth factors, and cytokines.

Furthermore, HA interacts with cell surface receptors, the most important of which is CD44. The HA–CD44 complex influences the cytoskeleton, adhesion, and migration of keratinocytes and helps maintain permeability barrier homeostasis. By interacting with other hyaluronan-binding proteins (hyaladherins), HA facilitates the organization of a dense, structured matrix in the intercellular space, which is critical for the mechanical integrity of the epidermis (Evrard C. et al., 2021).

It was long believed that HA was present only in the living layers of the skin; however, it has been shown that hyaluronan is present in small amounts in the normal stratum corneum (Sakai S. et al., 2000). In a healthy epidermis, HA located in the ECM of the underlying layers is captured and transported to the stratum granulosum as cells differentiate. There, under the action of hyaluronidase 1 (HYAL1), it is degraded into low-molecular-weight fragments (Malaisse J. et al., 2015). These fragments are found in the stratum corneum and likely contribute to skin hydration alongside natural moisturizing factor (NMF) components, supporting the normal plasticity and resistance of the stratum corneum (Sakai S. et al., 2000; Malaisse J. et al., 2015).

HA Metabolism in Atopic Dermatitis

HA synthesis is carried out by hyaluronan synthase enzymes (HAS1, HAS2, HAS3). In the normal adult epidermis, HAS1 is considered the primary source of HA, while HAS2 is expressed very weakly. In atopic dermatitis (AD), the picture changes radically: under the influence of pro-inflammatory cytokines, HAS1 activity drops, while HAS3 expression increases significantly (Evrard C. et al., 2021).

HAS3 primarily synthesizes low-molecular-weight HA. These short fragments act as damage-associated molecular patterns (DAMPs) and can activate TLR2 and TLR4 receptors, initiating inflammatory cascades. Thus, the shift toward HAS3 in AD contributes to the maintenance and amplification of chronic inflammation in the epidermis (Evrard C. et al., 2021).

HA Degradation and Its Link to Barrier Function

The half-life of HA in the epidermis is short, lasting 1–2 days (Fraser J.R. et al., 1997). Degradation is performed by the hyaluronidases HYAL1 and HYAL2. A key clinical point concerns the localization of HYAL1: this enzyme is primarily active in the cells of the stratum granulosum, near the epidermal barrier (Malaisse J. et al., 2015).

In AD, a disruption in the normal formation of the stratum granulosum (hypogranulosis) is often observed, leading to HYAL1 dysfunction. Experiments in HYAL1-deficient models have shown that the accumulation of high-molecular-weight HA in the stratum corneum (instead of normal short fragments) is accompanied by impaired epidermal barrier properties. Excessive HA in the stratum corneum may retain water too effectively, hindering the formation of normal hydrophobic protection and increasing skin permeability to allergens and pathogens (Sakai S. et al., 2000; Malaisse J. et al., 2015; Evrard C. et al., 2021).

HA and Spongiosis

In AD, increased HA synthesis and the predominance of low-molecular-weight fragments lead to HA accumulation in expanded intercellular spaces. This facilitates the formation of spongiosis, a characteristic intraepidermal edema. The increased intercellular volume eases the migration of immune cells and supports the inflammatory process, which, combined with defects in the lipid matrix, enhances transepidermal water loss (Evrard C. et al., 2021).

Therapeutic Opportunities: Topical and Systemic Hyaluronic Acid

Given HA's involvement in maintaining the epidermal ECM structure, intercellular adhesion, and water barrier homeostasis, the use of topical HA products as part of comprehensive AD care is logical. Research indicates that specific HA fractions can modulate the expression of key epidermal barrier proteins. Specifically, the application of low-molecular-weight HA fragments can stimulate the production of stratum corneum structural proteins by keratinocytes and influence the activity of enzymes required for ceramide synthesis. These effects are linked to the restoration of lamellar lipid secretion, which ensures skin hydrophobicity and impermeability.

Topical HA products can improve barrier function parameters, including reducing transepidermal water loss. It is important to note that the impact of different HA fractions on the epidermal barrier is not uniform, and molecular activity may depend on size. However, research indicates that external forms of HA can serve as an adjuvant care component to support barrier restoration and remission.

The use of oral HA is also discussed in the literature. Systemic influence on HA precursor metabolism has been shown to accelerate epidermal turnover and enhance endogenous HA synthesis in the skin. In the models included in the analysis, increased epidermal HA content was accompanied by more uniform hydration and improved structural organization of the upper skin layers. This effect is viewed as potentially beneficial for patients with chronic dermatoses accompanied by xerosis. However, the authors emphasize that data on oral HA use in AD require further clarification in clinical trial settings (Evrard C. et al., 2021).

Conclusion

Hyaluronic acid is an active regulator of the epidermal barrier. In atopic dermatitis, the shift in the HAS1/HAS3 enzyme balance and the disruption of HA degradation by HYAL1 are key factors in the development of inflammation and spongiosis. Correcting HA metabolism and utilizing its therapeutic forms represent a promising direction in adjuvant AD therapy, aimed at restoring skin integrity and reducing the antigenic load.

Refernces

1. Evrard C., Lambert de Rouvroit C., Poumay Y. Epidermal hyaluronan in barrier alteration-related disease. Cells 2021; 10(11): 3096.
2. Fraser J.R, Laurent T.C, Laurent U.B. Hyaluronan: Its nature, distribution, functions and turnover. J Intern Med 1997; 242(1): 27–33.
3. Tammi R., Ripellino J.A, Margolis R.U, Tammi M. Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe. J Invest Dermatol 1988; 90(3): 412–414.
4. Sakai S., Yasuda R., Sayo T. et al. Hyaluronan exists in the normal stratum corneum. J Invest Dermatol 2000; 114(6): 1184–1187.
5. Malaisse J., Evrard C., Feret D., et al. Hyaluronidase-1 is mainly functional in the upper granular layer, close to the epidermal barrier. J Invest Dermatol 2015; 135(12): 3189–3192.