Jean-Pierre Hachem

pH-regulated mechanisms account for pigment-type differences in epidermal barrier function.

To determine whether pigment type determines differences in epidermal function, we studied stratum corneum (SC) pH, permeability barrier homeostasis, and SC integrity in three geographically disparate populations with pigment type I-II versus IV-V skin (Fitzpatrick I-VI scale). Type IV-V subjects showed: (i) lower surface pH (approximately 0.5 U); (ii) enhanced SC integrity (transepidermal water loss change with sequential tape strippings); and (iii) more rapid barrier recovery than type I-II subjects. Enhanced barrier function could be ascribed to increased epidermal lipid content, increased lamellar body production, and reduced acidity, leading to enhanced lipid processing. Compromised SC integrity in type I-II subjects could be ascribed to increased serine protease activity, resulting in accelerated desmoglein-1 (DSG-1)/corneodesmosome degradation. In contrast, DSG-1-positive CDs persisted in type IV-V subjects, but due to enhanced cathepsin-D activity, SC thickness did not increase. Adjustment of pH of type I-II SC to type IV-V levels improved epidermal function. Finally, dendrites from type IV-V melanocytes were more acidic than those from type I-II subjects, and they transfer more melanosomes to the SC, suggesting that melanosome secretion could contribute to the more acidic pH of type IV-V skin. These studies show marked pigment-type differences in epidermal structure and function that are pH driven.

Proteolytically active allergens cause barrier breakdown.

Two major allergens--the house dust mite Dermatophagoides pteronyssinus (Der p 1) and cockroach allergens--are proteolytically active and stimulate the protease-activated receptor 2 (PAR-2). Jeong et al. (2008, this issue) exposed mouse and human epidermis to both allergens and correlated the observed delay in permeability barrier recovery to PAR-2 activation/signaling. This article exposes the secretive boundaries between barrier homeostasis and immunity.

Beneficial effects of a skin tolerance-tested moisturizing cream on the barrier function in experimentally-elicited irritant and allergic contact dermatitis

In experimentally‐induced irritant (ICD) and allergic (ACD) contact dermatitis, an oil‐in‐water (o/w) cream was applied to investigate its effects on a disturbed barrier function compared to untreated physiological barrier repair. Transepidermal water loss (TEWL) measurements were performed. Before the start of the experiments, the skin tolerance of the cream was examined, revealing the non‐irritating characteristics of the ingredients and the absence of any contact allergic patch test reaction. In the ICD study, sodium lauryl sulfate (SLS) patches were applied to the forearms of young female volunteers. Consequently, it was observed that repeated cream application (14 days, 2×/day) significantly improved the TEWL of SLS‐damaged skin, leading to a complete recovery on day 15. In the ACD study, disruption of skin barrier function was obtained by a nickel‐mediated contact allergy patch (CAP) test. The cream was then applied 2×/day for 4 consecutive days. Assessment of TEWL clearly showed that recovery of the disrupted skin significantly improved after cream application in comparison to untreated barrier repair.

Topical Peroxisome Proliferator Activated Receptor Activators Accelerate Postnatal Stratum Corneum Acidification

Previous studies have shown that pH declines from between 6 and 7 at birth to adult levels (pH 5.0-5.5) over 5-6 days in neonatal rat stratum corneum (SC). As a result, at birth, neonatal epidermis displays decreased permeability barrier homeostasis and SC integrity, improving days 5-6. We determined here whether peroxisome proliferator-activated receptor (PPAR) activators accelerate postnatal SC acidification. Topical treatment with two different PPARalpha activators, clofibrate and WY14643, accelerated the postnatal decline in SC surface pH, whereas treatment with PPARgamma activators did not and a PPARbeta/delta activator had only a modest effect. Treatment with clofibrate significantly accelerated normalization of barrier function. The morphological basis for the improvement in barrier function in PPARalpha-treated animals includes accelerated secretion of lamellar bodies and enhanced, postsecretory processing of secreted lamellar body contents into mature lamellar membranes. Activity of beta-glucocerebrosidase increased after PPARalpha-activator treatment. PPARalpha activator also improved SC integrity, which correlated with an increase in corneodesmosome density and increased desmoglein-1 content, with a decline in serine protease activity. Topical treatment of newborn animals with a PPARalpha activator increased secretory phospholipase A2 activity, which likely accounts for accelerated SC acidification. Thus, PPARalpha activators accelerate neonatal SC acidification, in parallel with improved permeability homeostasis and SC integrity/cohesion. Hence, PPARalpha activators might be useful to prevent or treat certain common neonatal dermatoses.

Efficacy of topical corticosteroids in nickel-induced contact allergy

Summary  In this study we used the nickel contact allergy patch (CAP) test to investigate the effect of topical corticosteroids on allergic contact dermatitis (ACD). On day 1, three CAP tests were applied for 48 h on the forearms of 20 female volunteers with a known nickel ACD. CAP of the right forearm contained 5% nickel, and of the left forearm physiological saline. Clinical scoring, transepidermal water loss and skin hydration were measured on day 1 before CAP application, on day 4 (0, 2 and 6 h) after ACD and from days 5 to 8 (0 h). A topical corticosteroid and its vehicle were applied twice daily starting from day 4 on two ACD sites. Transepidermal water loss values were significantly decreased on the topical‐corticosteroid‐treated sites in the early phase of ACD (day 4, 6 h after the first application) while clinical efficacy showed significant improvement on days 7 and 8. The vehicle was found to improve skin hydration only on day 8. In conclusion the topical corticosteroid improved the skin barrier function in the early inflammatory phase of ACD (day 4, 6 h). The lack of improvement in transepidermal water loss in the later phase of ACD might be accounted for by the secondary effects of the corticosteroid on proliferation and differentiation of keratinocytes.

Caspase-14-Deficient Mice Are More Prone to the Development of Parakeratosis

Caspase-14 is an important protease in the proper formation of a fully functional skin barrier. Newborn mice that are deficient in caspase-14 exhibit increased transepidermal water loss and are highly sensitive to UVB-induced photodamage. Decreased caspase-14 expression and incomplete caspase-14 processing in lesional psoriatic parakeratotic stratum corneum has been reported previously. In this study, we show that caspase-14-deficient skin frequently displays incompletely cornified cells in the transitional zone between the granular and the cornified layers, pointing to a delay in cornification. We also demonstrate that after challenge of epidermal permeability barrier function by repetitive acetone treatment, a higher incidence of large parakeratotic plaques was observed in caspase-14-deficient skin. Furthermore, caspase-14-deficient mice are more prone than control mice to the development of parakeratosis upon induction of psoriasis-like dermatitis by imiquimod treatment. These results show that lack of caspase-14 expression predisposes to the development of parakeratosis and that caspase-14 has an important role in keratinocyte terminal differentiation and the maintenance of normal stratum corneum, especially in conditions causing epidermal hyperproliferation.

Epidermal ceramidase activity regulates epidermal desquamation via stratum corneum acidification.

The acidic pH of the outer surface of the mammalian skin plays several important roles in the epidermal barrier function. The 2 endogenous pathways that are currently known to elicit this acidic pH are the generation of free fatty acids from phospholipids and the exchange of protons for sodium ions by non-energy-dependent sodium-proton exchangers. In this study, we propose a third endogenous pathway, i.e. epidermal ceramidase activity, generating free fatty acids from ceramides. By topical application of N-oleylethanolamine, a well-known ceramidase inhibitor, we could demonstrate a significant increase in the stratum corneum pH and a corresponding decrease in the epidermal free fatty acid content. Moreover, we could show that the resulting change in the apparent skin pH also provoked a delay in early barrier recovery and an increased epidermal desquamation, corresponding to earlier observations made for the already known endogenous mechanisms.

Effect of rice starch as a bath additive on the barrier function of healthy but SLS-damaged skin and skin of atopic patients.

Rice starch added to bath water was studied for its possible beneficial effects on impaired barrier function as evaluated by transepidermal water loss measurements. The forearm skin of healthy volunteers was irritated by sodium lauryl sulphate. Exposure to rice-starch-containing bath water--twice daily for 15 min--led to a 20% improvement on the healing capacity of damaged skin. The beneficial effect was also observed for a rice-starch-containing lipid-free bath formulation, and an oil-in-water bath lotion enriched with evening primrose oil. Skin barrier function in patients with atopic dermatitis also improved after the addition of starch powder to bath water. Rice starch in powder or formulated in a bath product can therefore be recommended as a skin repair bathing additive for barrier damaged skin, particularly in the case of atopic dermatitis patients.

Combination Therapy Improves the Recovery of the Skin Barrier Function: An Experimental Model Using a Contact Allergy Patch Test Combined with TEWL Measurements

Background: Nickel (Ni) allergic contact dermatitis (ACD) alters the skin barrier. Objective: Our aim was to compare the efficacy of combination therapies on ACD, using a topical corticosteroid and a corneotherapy agent (barrier cream), with that of a single therapy with corticosteroids. Methods: On day 1, 3 Ni test patches were applied on each forearm of 14 Ni-patch-test-positive females. Four contained 5% Ni and 2 physiological saline. Either topical corticosteroid or barrier cream were matched with the combination of both products on 3 of the 4 Ni ACD. The fourth was not treated. Clinical scoring, transepidermal water loss (TEWL) and stratum corneum (SC) capacitance were measured before (day 1) and after (days 4–8) ACD. Results: The combination therapy showed a significant decrease in TEWL values and an increase in SC capacitance. Conclusion: Combining a topical corticosteroid with corneotherapy agents prevents the delay in the healing process of skin barrier disruption due to ACD.

Cannabinoid receptors 1 and 2 oppositely regulate epidermal permeability barrier status and differentiation

Cannabinoid receptors (CBR) 1 and 2 have been implicated in keratinocyte differentiation/proliferation. How CB receptors affect epidermal permeability barrier and stratum corneum structure and function remains unclear. Permeability barrier abrogation was induced by sequential tape‐stripping of the SC and assessed in both CB1R and CB2R knockout (−/−) mice in comparison with wild‐type (+/+) littermates. Absence of CB1R delays permeability barrier recovery, while the latter was found to be accelerated in CB2R −/− mice. While increased lamellar body (LB) secretion is observed in CB2R −/− mice accounting for the enhanced recovery, CB1R −/− animals display strong alterations in lipid bilayer structures. Markers for epidermal differentiation (i.e. filaggrin, loricrin and involucrin) and terminal differentiation (i.e. TUNEL assay and caspase‐14 activation) were respectively decreased and increased in CB1R and CB2R −/− mice. Surprisingly, CB1R agonist treatment of human cultured keratinocytes increases mRNA of p21 and cytokeratin 1 and 10 and decreases cyclin D1 but protein levels remained unchanged. Such paradox could partially be explained by the increase in non‐phosphorylated‐4E‐BP1, an inhibitor of mRNA translation, following CB1R agonist treatment. Altogether, these observations put forward the importance and the complexity of cannabinoid signalling for the regulation of permeability barrier and epidermal differentiation.