title: Basis for enhanced barrier function of pigmented skin.
abstract: Humans with darkly pigmented skin display superior permeability barrier function in comparison with humans with lightly pigmented skin. The reduced pH of the stratum corneum (SC) of darkly pigmented skin could account for enhanced function, because acidifying lightly pigmented human SC resets barrier function to darkly pigmented levels. In SKH1 (nonpigmented) versus SKH2/J (pigmented) hairless mice, we evaluated how a pigment-dependent reduction in pH could influence epidermal barrier function. Permeability barrier homeostasis is enhanced in SKH2/J versus SKH1 mice, correlating with a reduced pH in the lower SC that colocalizes with the extrusion of melanin granules. Darkly pigmented human epidermis also shows substantial melanin extrusion in the outer epidermis. Both acute barrier disruption and topical basic pH challenges accelerate reacidification of SKH2/J (but not SKH1) SC, while inducing melanin extrusion. SKH2/J mice also display enhanced expression of the SC acidifying enzyme, secretory phospholipase A2f (sPLA2f). Enhanced barrier function of SKH2/J mice could be attributed to enhanced activity of two acidic pH-dependent, ceramide-generating enzymes, β-glucocerebrosidase and acidic sphingomyelinase, leading to accelerated maturation of SC lamellar bilayers. Finally, organotypic cultures of darkly pigmented human keratinocytes display enhanced barrier function in comparison with lightly pigmented cultures. Together, these results suggest that the superior barrier function of pigmented epidermis can be largely attributed to the pH-lowering impact of melanin persistence/extrusion and enhanced sPLA2f expression.
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Mao-Qiang
authors.initials: MQ
authors.lastname: Man
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA; Graduate Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan; Department of Dermatology, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan.
authors.forename: Tzu-Kai
authors.initials: TK
authors.lastname: Lin
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Santiago
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Celli
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Huang
authors.affiliation: Department of Dermatology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Truus
authors.initials: T
authors.lastname: Roelandt
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hupe
authors.affiliation: Department of Research and Development, The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.affiliation: Department of Research and Development, The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Silva
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA; Department of Dermatology, Hospital del Mar-IMIM, Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Martin-Ezquerra
authors.affiliation: ISDIN, Research & Development, Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Trullas
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sun
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Wakefield
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Wei
authors.affiliation: Medical Service, Department of Veterans Affairs Medical Center, and Department of Metabolism, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Theodora M
authors.initials: TM
authors.lastname: Mauro
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, San Francisco, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA. Electronic address: eliasp@derm.ucsf.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
mesh_terms: D000143:Acids / Q000378:metabolism*; D000818:Animals; D002518:Ceramides / Q000096:biosynthesis; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000648:ultrastructure; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D005962:Glucosylceramidase / Q000378:metabolism; D054501:Group II Phospholipases A2 / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015603:Keratinocytes / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D008297:Male; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism* / Q000648:ultrastructure; D008812:Mice, Hairless; D008854:Microscopy, Electron; D009924:Organ Culture Techniques; D019899:Paracrine Communication / Q000502:physiology; D010539:Permeability; D012880:Skin Pigmentation / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D000143:Acids; D002518:Ceramides; D008051:Lipid Bilayers; D008543:Melanins; D054501:Group II Phospholipases A2; C516297:Pla2g2f protein, mouse; D013108:Sphingomyelin Phosphodiesterase; D005962:Glucosylceramidase
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