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Review
. 2024 Feb;36(1):1-8.
doi: 10.5021/ad.23.078.

Importance of Stratum Corneum Acidification to Restore Skin Barrier Function in Eczematous Diseases

Eung Ho Choi  1 , Hyun Kang  2
Affiliations
Review

Importance of Stratum Corneum Acidification to Restore Skin Barrier Function in Eczematous Diseases

Eung Ho Choi et al. Ann Dermatol. 2024 Feb.

Abstract

Skin barrier function relies on three essential components: stratum corneum (SC) lipids, natural moisturizing factors (NMFs), and the acidic pH of the SC surface. Three endogenous pathways contribute to acidity: free fatty acids from phospholipids, trans-urocanic acid from filaggrin (FLG), and the sodium-proton antiporter (NHE1) activity. An acidic SC environment boosts the activity of enzymes to produce ceramides, which are vital for skin health. Conversely, an elevated pH can lead to increased skin infections, reduced lipid-processing enzyme activity, impaired permeability barrier recovery, and compromised integrity and cohesion of the SC due to increased serine protease (SP) activity. Elevated SC pH is observed in neonatal, aged, and inflamed skin. In atopic dermatitis (AD), it results from decreased NMF due to reduced FLG degradation, decreased fatty acids from reduced lamellar body secretion, and reduced lactic acid due to decreased sweating. Moreover, the imbalance between SP and SP inhibitors disrupts barrier homeostasis. However, acidifying the SC can help restore balance and reduce SP activity. Acidic water bathing has been found to be safe and effective for AD. In three different AD murine models, SC acidification prevented the progression of AD to respiratory allergies. In aging skin, a decrease in NHE1 leads to an increased skin pH. Mild acidic skin care products or moisturizers containing NHE1 activators can normalize skin pH and improve barrier function. In conclusion, maintaining the acidity of the SC is crucial for healthy skin barrier function, leading to significant benefits for various skin conditions, such as AD and aging-related skin issues.

Keywords: Atopic dermatitis; Epidermal barrier; Skin aging; Sodium-proton antiporter; Staratum corneum.

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Conflict of interest statement

The authors have nothing to disclose.

Figures

Fig. 1
Fig. 1. Skin barrier is composed of SC and tight junction. In the SC, corneocytes, SC intercellular lipid lamellae, and corneodesmosomes are the major components of the skin barrier. Filaggrin is the main protein in the corneocyte. Ceramide is the most abundant lipid in the SC. Proteases such as SCCE encoded by the KLK7 gene degrade the corneodesmosomes. Serine protease inhibitors such as LEKTI encoded by SPINK5 inhibit the protease activity. All of these are related to SC pH.
SC: stratum corneum, SCCE: stratum corneum chymotryptic enzyme, KLK7: kallikrein 7, LEKTI: Lympho-epithelial Kazal-type-related inhibitor, SPINK5: serine protease inhibitor Kazal-type 5.
Fig. 2
Fig. 2. For healthy skin barrier function, 3 components must be maintained properly. They are SC lipids for normal TEWL, NMFs for SC hydration, and acidic SC for skin surface pH.
SC: stratum corneum, TEWL: transepidermal water loss, NMF: natural moisturizing factor.
Fig. 3
Fig. 3. Maintaining an acidic pH in the SC is important for establishing a healthy skin barrier. The SC exhibits a pH gradient, with a decrease in pH as it gets closer to the surface. To maintain the acid mantle of the SC, sebum-derived free fatty acids and sweat-derived lactic acid are also important as well as 3 endogenous pathways. Three endogenous pathways include 1) the non-energy-dependent Na+/H+ antiporter, NHE1, 2) the generation of free fatty acids from phospholipids by sPLA2, 3) the generation of urocanic acid from histidine by histidase. Deterioration of any of these pathways leads to an elevation in SC pH, which is linked to the alteration of permeability barrier homeostasis and SC integrity/cohesion.
SC: stratum corneum, sPLA2: secretory phospholipase A2, SG: stratum granulosum.
Fig. 4
Fig. 4. The functional consequences of elevated pH of SC. Elevated pH of the SC not only inactivates lipid-processing enzymes but also elevates the activity of SP. Increased SPs directly decrease lipid-processing enzymes, degrade CD-forming proteins, and inhibit the secretion of LB. Therefore, the functional consequences are 1) negative effects on the skin microbiota, 2) delayed barrier recovery, and 3) reduced SC integrity/cohesion.
SC: stratum corneum, SP: serine protease, LB: lamellar body, CD: corneodesmosome.
Fig. 5
Fig. 5. The imbalance between SP and SPI in the skin barrier homeostasis is observed in the patients with AD (modified from Choi and Yoon42). Many AD patients are known to have genetic mutations associated with skin barrier defects. AD patients with mutations in the FLG gene exhibit an elevated pH in the skin due to barrier disruption and filaggrin deficiency. On the other hand, AD patients with mutations in the SPINK5 gene experience uncontrolled activity of SPs following the pH elevation. The uncontrolled SP activity subsequently activates PAR-2, leading to the increased production of TSLP. This, in turn, activates LCs and further stimulates Th2 lymphocytes, resulting in the development of allergic inflammation. Therefore, these 3 points in this pathway could become therapeutic targets. As shown in this figure, lowering the SC pH can potentially correct the subsequent pathways.
SP: serine proteinase, SPI: serine proteinase inhibitor, AD: atopic dermatitis, FLG: filaggrin, SPINK5: serine peptidase inhibitor Kazal type 5, PAR-2: protease-activated receptor-2, TSLP: thymic stromal lymphopoietin, LC: Langerhans cell, LEKTI: Lympho-epithelial Kazal-type-related inhibitor, LB: lamellar body.
Fig. 6
Fig. 6. Maintaining an acidic environment on the SC inhibits the atopic march pathway. Three kinds of AD murine models (Ox-AD, NC/Nga, and Flaky tail mice) allowed us to observe the progression of respiratory allergies following exposure to the HDM antigen. The maintenance of a neutral skin environment exacerbates the progression of AD to respiratory allergies (the atopic march). Application of HDM antigen to the AD-like skin lesions and respiratory system of the mice resulted in the development of respiratory allergies. This was evidenced by the presence of airway eosinophilia and increased expression of PAR-2 and TSLP in the lung tissue, which are indicative of allergic inflammation and sensitization. This suggests that promoting an acidic environment on the skin might serve as a novel intervention method to impede the progression of AD to respiratory allergies, thereby inhibiting the atopic march.
SC: stratum corneum, AD: atopic dermatitis, HDM: house dust mite, PAR-2: protease-activated receptor-2, TSLP: thymic stromal lymphopoietin, Ox-AD: oxazolone-induced atopic dermatitis, IgE: immunoglobulin E.
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