Evidence for the Existence of a Self-Regulated Enzymatic Process Within the Human Stratum Corneum –An Unexpected Role for Urocanic Acid

Abstract

The existence of a flux of proton donors from skin (inner part of the forearm) to the electrode was observed in 12 male and female volunteers. This flux was used to collect and identify the ionic species responsible for skin acidity. It was then found that: (i) pK of these proton donors (pK = 6.13 +/- 0.07) was quasi-identical to that of trans-urocanic acid (6.10), and (ii) the amount of urocanic acid present in stratum corneum was sufficient in itself to explain the acidic level as measured with pH meter (R = 0.8484, n = 10, p = 0.00136). As a result, the contribution of other ionic species can be considered as negligible in normal human skin. The data recorded led us to identify three groups (Fast, Medium, and Slow) characterized by different skin surface pH values (low, medium, and close to neutral) and showing a pH gradient in the outer layers of the stratum corneum, or not. Data analysis suggests that these characteristics depend on urocanic acid production rate within the stratum corneum and that this production rate is self-regulated by its urocanic acid content.

Filaggrin Genotype in Ichthyosis Vulgaris Predicts Abnormalities in Epidermal Structure and Function

“…72,73 Accordingly, SC hydration declined by about 30% in doubleallele IV subjects in comparison to wild-type controls ( Figure 2D), but reductions in hydration levels did not achieve statistical significance in single-allele subjects. By steepening the gradient of water loss across the SC, decreased SC hydration alone likely also places further stress on the permeability barrier in IV.…”

Neonatal Development of the Stratum Corneum pH Gradient: Localization and Mechanisms Leading to Emergence of Optimal Barrier Function

“…In addition, primarily catabolic processes within the SC generate acidic end-products that can affect SC pH. Two prominent examples for these intrinsic processes are: (1) the breakdown o proteins such as filaggrin to produce urocanic acid (Krien and Kermici, 2000); and (2) the hydrolysis of lipids, such as PL, to yield FFA (Fluhr et al, 2001). The latter may occur cither intrinsically through specific phospholipascs (Schadow et al, 2001), or extrinsically as byproducts of microbial metabolism (Korting et al, 1987).…”

“…This localization further excludes the above-mentioned extrinsic pathways, as these would acidify the SC in an outside-in manner. Further, the localization of acidity in the lower SC docs not appear compatible with the intrinsic process of urocanic acid generation (Krien and Kermici, 2000), which should be localized to, or at least originate from, the intracellular compartment of the corneocytc, which in all our FLIM experiments appears as a domain of neutral pH (compare e.g., pH maps in Fig 4, and Hanson et al, 2002)). …”

NHE1 Regulates the Stratum Corneum Permeability Barrier Homeostasis

“…cUCA generation in SC as a mechanism for acidification, while providing a compelling mathematical concept (12), to date has not been thoroughly tested. Further, it cannot explain acidification at the SG-SC interface but rather complies with the conventional view of an inner-to-outer SC pH gradient.…”

“…The acidic pH of the SC has been attributed largely to mechanisms extrinsic to the epidermis, such as: (a) byproducts of microbial metabolism (8); (b) lactic acid and lactate from sweat (9); (c) free fatty acids (10); (d) progressive desiccation of the SC (11), and/or (e) generation of the organic acid, cis-urocanic acid (cUCA) from filaggrin (12). In this report, we demonstrate that NHE1 deletion or pharmacologic inhibition elevates SC pH and impedes both lipid processing and resulting barrier repair, suggesting this agent is essential in establishing and/or maintaining SC pH.…”