Roshan Gunathilake, Nanna Y. Schurer, Brenda A

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Basis for Enhanced Barrier Function of Pigmented Skin

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pH-Regulated Mechanisms Account for Pigment-Type Differences in Epidermal Barrier Function Roshan Gunathilake, Nanna Y. Schurer, Brenda A. Shoo, Anna Celli, Jean-Pierre Hachem, Debra Crumrine, Ganga Sirimanna, Kenneth R. Feingold, Theodora M. Mauro, Peter M. Elias Journal of Investigative Dermatology Volume 129, Issue 7, Pages 1719-1729 (July 2009) DOI: 10.1038/jid.2008.442 Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Type IV–V subjects show faster barrier recovery kinetics, and better SC integrity and cohesion. The volar forearms of pigment types I–II and IV–V subjects were tape-stripped until TEWL was increased threefold. TEWL was measured immediately, and 24, 48, and 72hours, after acute barrier disruption. For calculation of the percentage change in TEWL, the following formula was used: (TEWL immediately after stripping-TEWL at the indicated time)/(TEWL immediately after stripping-baseline TEWL) × 100%. Baseline TEWL for the two populations was normal (≤10gm-2hour-1). Type IV–V subjects (a) showed significantly faster epidermal barrier recovery at 24, 48, and 72hours, (b) needed a significantly higher number of tape strippings to produce a comparable barrier disruption, and (c) had significantly less protein removed per tape stripping. Results shown represent means±SEM. Journal of Investigative Dermatology 2009 129, 1719-1729DOI: (10.1038/jid.2008.442) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Epidermal functional differences among divergent pigment groups are independent of geographic location and occupation. Barrier recovery, epidermal integrity, and forearm surface pH were assessed in a cohort of subjects with type I–II and IV–V skin, living in the same geographic location (San Francisco, CA). None of the subjects were involved in nursing or related occupations. SC integrity was assessed as the number of D-squame tape strippings required to increase TEWL by threefold. TEWL was assessed immediately and 3hours after barrier disruption and percentage of recovery was calculated as described previously. The baseline TEWL for the two pigment groups was ≤10gm-2hour-1. Surface pH of the volar forearm was measured using a flat glass electrode. Journal of Investigative Dermatology 2009 129, 1719-1729DOI: (10.1038/jid.2008.442) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Type IV–V subjects have more acidic SC surface pH. Surface pH of the (a) volar forearm and (b) dorsum of the hand was measured in two age-matched groups of German (n=110, 72 females, age 29±6.6) and Sri Lankan (n=129, 117 females, age 25±2.1) nurses with type I–II and IV–V skin using a flat glass electrode. Type IV–V subjects had significantly more acidic surface pH. Results shown represent means±SEM. Journal of Investigative Dermatology 2009 129, 1719-1729DOI: (10.1038/jid.2008.442) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Darkly pigmented subjects have more lamellar bodies (LBs) and barrier lipids. (a–c) The darkly pigmented skin has higher LB density as illustrated by random electron micrographs (a, b: osmium tetroxide postfixation, Bar=1μm), and assessed by quantitative electron microscopy. (c) The granular layer immediately below the SC–SG junction is shown. Block arrows point to LBs. Results shown represent means±SEM. (d, e) This finding correlated with increased SC lipid content as shown by Nile Red fluorescence in frozen sections. Bar=40μm. Journal of Investigative Dermatology 2009 129, 1719-1729DOI: (10.1038/jid.2008.442) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Persistence of corneodesmosomes (CDs) in the upper SC of darkly pigmented skin is paralleled by decreased SP dependent degradation of Desmosglein-1 (DSG-1). (a–c) Darkly pigmented subjects have significant retention of CDs in the upper SC as shown by quantitative electron microscopy. In contrast, the CDs in the upper SC of lightly pigmented skin appeared to be degraded osmium tetroxide postfixation (Bar=1μm). CD and cornified envelope (CE) length was measured in sequential electron micrographs by planimetry, and CD length was expressed as a percentage of CE length. Results shown represent means±SEM. (d) Immunofluorescence staining shows parallel retention of DSG-1 in the SC of darkly pigmented skin despite comparable DSG-1 expression at stratum granulosum level. Bar=40μm. Journal of Investigative Dermatology 2009 129, 1719-1729DOI: (10.1038/jid.2008.442) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Serine protease inactivation by more acidic surface pH accounts for persistence of corneodesmosomes in the upper SC in darkly pigmented subjects, but increased acidic-dependent protease activity maintains normal SC thickness. (a) Type IV–V darkly pigmented subjects with more acidic surface pH have lower SP activity under basal conditions as shown by in situ zymography. Inset: in vitro neutralization of sections with 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer (pH 7) induced SP activity to comparable levels, showing that differences in activity are pH driven, rather than being attributable to different levels of enzyme protein. Bar=40μm. (b) In situ zymography of frozen sections shows increased activity of cathepsin D, an aspartate protease with acidic pH optimum, in darkly pigmented skin. Bar=40μm. Journal of Investigative Dermatology 2009 129, 1719-1729DOI: (10.1038/jid.2008.442) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Single applications of either polyhydroxyl acids decrease SC pH and accelerate barrier recovery in lightly pigmented subjects. (a–c) Lactobionic acid (LBA, 5% in propylene glycol/ethanol: 70/30), gluconolactone (GL), neutralized LBA, neutralized GL, or vehicle (V) was applied on the forearm skin of human volunteers (n=16). Although basal values were identical on all test sites before application (not shown), significant decreases in surface pH were observed at 1, 6, and 24hours following single application of either LBA or GL acids compared with the vehicle. (d) TEWL was measured before and at 0, 3, 24, and 48hours following acute barrier disruption by repeated cellophane tape stripping on the forearms of type I–II subjects. Acidification of SC pH by PHA (LBA or GL, n=16) significantly improved barrier recovery in comparison with vehicle (neutralized LBA/neutralized GL)-treated skin sites. Journal of Investigative Dermatology 2009 129, 1719-1729DOI: (10.1038/jid.2008.442) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Melanocytic dendrites are significantly more acidic in the darkly pigmented subjects. (a) Two-channel confocal imaging of human melanocytes stained with the pH-sensitive probe SNARF-5F shows that dendrites, but not the cell bodies, of darkly pigmented melanocytes (taken from type IV–V skin) are significantly more acidic, in comparison with those of lightly pigmented melanocyte (taken from type I–II skin). The color bar on the left of the image indicates the pH range corresponding to the R color-coding used in the figures, with green indicating more acidic pH, while yellow denotes more neutral pH. Bar=15μm. (b) The spectral changes in the SNARF-5F emission were used to quantify R, and R values were used to derive pH (see under Materials and methods). Both the cytosol and dendrites were significantly more acidic in the darkly pigmented melanocytes. Journal of Investigative Dermatology 2009 129, 1719-1729DOI: (10.1038/jid.2008.442) Copyright © 2009 The Society for Investigative Dermatology, Inc Terms and Conditions