Acute Acidification of Stratum Corneum Membrane Domains Using Polyhydroxyl Acids Improves Lipid Processing and Inhibits Degradation of Corneodesmosomes

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Acute Acidification of Stratum Corneum Membrane Domains Using Polyhydroxyl Acids Improves Lipid Processing and Inhibits Degradation of Corneodesmosomes Jean-Pierre Hachem, Truus Roelandt, Nanna Schürer, Xu Pu, Joachim Fluhr, Christina Giddelo, Mao-Qiang Man, Debra Crumrine, Diane Roseeuw, Kenneth R. Feingold, Theodora Mauro, Peter M. Elias Journal of Investigative Dermatology Volume 130, Issue 2, Pages 500-510 (February 2010) DOI: 10.1038/jid.2009.249 Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Polyhydroxyl acids (PHA) produce a sustained decrease in SC pH at all levels of the murine stratum corneum. Either lactobionic acid (LBA) and gluconolactone (GL) 10% was applied on murine flanks. (a) The decrease in surface SC pH is significant at 3hours after PHA application in comparison with neutralized (n)-LBA and nGL. (b) Surface pH recovers between 16 and 35hours post single application of LBA. (c) LBA-induced acidification extends deep into the SC after application of LBA as shown by the surface pH measurement after sequential tape stripping. (d) Similarly, FLIM measurements show that LBA treatment decreased pH within both the cytosolic (intracellular: IC) and membrane microdomains (extracellular: EC) at all levels of murine SC (by about 0.5 pH unit). LBA further acidified membrane microdomains in the lower SC (by about 1 pH unit), extending downward to the SG–SC interface. Results shown in as the mean±SEM (n=4–6). Journal of Investigative Dermatology 2010 130, 500-510DOI: (10.1038/jid.2009.249) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 FLIM imaging. Fluorescence Lifetime Imaging (FLIM) of unperturbed stratum corneum treated with LBA vs normalized LBA (nLBA), used as a control. A series of five optical sections is shown, starting at the skin surface (top) and extending to the SG (8μm). Images are shown en face, and pH is measured by assessing the lifetime of the pH-sensitive moderator BCECF. Intensity imagines (lower two rows) are compared with lifetime images (upper two rows). Light blue represents more neutral values, whereas green and yellow represent more acidic values. Amorphous acidic collections are seen on the surface of the LBA but not on the nLBA-treated skin, likely corresponding to topically applied LBA. Owing to LBA, extracellular acidity is more visible in the LBA-treated SC, although acidification diminishes at the SG, likely representing decreased LBA diffusion at deeper SC/SG levels. Bar=10μm. Journal of Investigative Dermatology 2010 130, 500-510DOI: (10.1038/jid.2009.249) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Hyperacidification accelerates barrier recovery in murine skin. TEWL was measured before and at 0, 3, 24, and 48hours after acute barrier disruption by repeated Cellophane tape stripping on hairless mouse flanks. Similarly, single application of either LBA (a) or GL (b) 10% immediately after tape stripping to hairless mouse flanks significantly accelerated barrier recovery kinetics 3hours after disruption in comparison with nLBA, air exposed (AE), V, or nGL. Results shown in as the mean±SEM (n=4–6). Journal of Investigative Dermatology 2010 130, 500-510DOI: (10.1038/jid.2009.249) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Hyperacidification-induced acceleration in barrier recovery is attributable to accelerated lamellar membrane maturation consequent to β-GlcCer'ase and aSMase activities. (a) LBA application immediately after tape stripping of normal murine skin, accelerated processing of lamellar bilayers at the stratum corneum–stratum granulosum (SC–SG) interface (shown by white arrowheads on LBA-treated sites in right panel) in comparison with nLBA-treated (left panel) 3hours after acute barrier disruption. RuO4 post-fixation. Bar=200nm. (b) Accelerated maturation of lamellar bilayers to an increased in situ activity of β-GlcCer'ase and aSMase in outer SG/inner SC interface 3hours after acute barrier disruption in comparison with nLBA treatment. The increase in β-GlcCer'ase and aSMase activities is pH-dependent and not consequent on an increase in enzyme mass, as in situ neutralization downregulates activities of both enzymes to the initial basal level. Journal of Investigative Dermatology 2010 130, 500-510DOI: (10.1038/jid.2009.249) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Pre-acidification improves SC integrity/cohesion. To assess the effects of skin acidification on SC integrity/cohesion, LBA and GL were applied to hairless mice flanks. Integrity (a) markedly improved in the lower SC 3hours after a single application of LBA and GL. Similarly, a 3-hour exposure of normal skin to either LBA or GL significantly improved SC cohesion (b), again at the lower levels of the SC. Results shown as the mean±SEM. Journal of Investigative Dermatology 2010 130, 500-510DOI: (10.1038/jid.2009.249) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Corneodesmosome (CD) density is increased following acute SC acidification. (a) Quantitative EM analysis shows a significant increase in CD density on LBA-treated skin sites compared with nLBA treatment. (b) The number of CD (arrows) is increased and the lower SC appears more compacted in LBA-treated sites shown by the increased number of inter-corneocyte hooks (asterisks). Bar=0.25μm. (c) Western immunoblotting for DSG1 is reduced in the lower SC in LBA-treated mice compared with vehicle treatment, whereas upper SC DSG1 are relatively protected from degradations. Yet induction of DSG3 expression is observed in LBA-treated animals (V=vehicle: propylene glycol: ethanol). Journal of Investigative Dermatology 2010 130, 500-510DOI: (10.1038/jid.2009.249) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Exposure of normal skin to acid pH is followed by a decrease in basal serine protease (SP) activity and kallikrein (klk) 5 and 7 activation. (a and b) In situ zymography for serine protease (SP) and soybean trypsin inhibitor (STI) binding assay 3hours after PHA treatment shows a decrease in SP activity on SC acidification sites: LBA- vs nLBA-treated sites. The decrease in SP activities is not due to a decrease in enzyme mass as in situ neutralization overrides LBA effect by reactivating SP. Yet fluorescent pepstatin A binding assay (c) was carried out on sections from LBA, nLBA-treated normal skin or nLBA-treated tape-stripped (TS) skin to assess cathepsin D activity. Unlike barrier abrogation (TS+nLBA), SC acidification alone does suffice to increase enzyme activity, suggesting a secondary trigger besides pH for cathepsin D activation. (d) Western immunoblotting for klk7 and 5 shows decreased immunostaining for the active forms for both proteases (23 and 31kDa, respectively) in the non-lipid raft (LR) fraction. Note the restriction of pro-klk5 and 7 to the LR domains. A similar pattern of pro-cathespin D (52kDa) expression with a virtually absent active cathepsin D on both LBA- and nLBA-treated sites was found. Unlike klk5 and 7, pro-cathespin D is restricted to non-LR domains. Journal of Investigative Dermatology 2010 130, 500-510DOI: (10.1038/jid.2009.249) Copyright © 2010 The Society for Investigative Dermatology, Inc Terms and Conditions