title: NHE1 regulates the stratum corneum permeability barrier homeostasis. Microenvironment acidification assessed with fluorescence lifetime imaging.
abstract: The outermost epidermal layer, the stratum corneum (SC), exhibits an acidic surface pH, whereas the pH at its base approaches neutrality. NHE1 is the only Na(+)/H(+) antiporter isoform in keratinocytes and epidermis, and has been shown to regulate intracellular pH. We now demonstrate a novel function for NHE1, as we find that it also controls acidification of extracellular "microdomains" in the SC that are essential for activation of pH-sensitive enzymes and the formation of the epidermal permeability barrier. NHE1 expression in epidermis is most pronounced in granular cell layers, and although the surface pH of NHE1 knockout mice is only slightly more alkaline than normal using conventional pH measurements, a more sensitive method, fluorescence lifetime imaging, demonstrates that the acidic intercellular domains at the surface and of the lower SC disappear in NHE1 -/- animals. Fluorescence lifetime imaging studies also reveal that SC acidification does not occur through a uniform gradient, but through the progressive accumulation of acidic microdomains. These findings not only visualize the spatial distribution of the SC pH gradient, but also demonstrate a role for NHE1 in the generation of acidic extracellular domains of the lower SC, thus providing the acidification of deep SC interstices necessary for lipid processing and barrier homeostasis.
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center and Department of Dermatology, University of California, San Francisco, California 94121, USA. behnemj@itsa.ucsf.edu
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Behne
authors.forename: Jamie W
authors.initials: JW
authors.lastname: Meyer
authors.forename: Kerry M
authors.initials: KM
authors.lastname: Hanson
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Barry
authors.forename: Satoru
authors.initials: S
authors.lastname: Murata
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.forename: Robert W
authors.initials: RW
authors.lastname: Clegg
authors.forename: Enrico
authors.initials: E
authors.lastname: Gratton
authors.forename: Walter M
authors.initials: WM
authors.lastname: Holleran
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Theodora M
authors.initials: TM
authors.lastname: Mauro
mesh_terms: D000818:Animals; D004817:Epidermis / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010539:Permeability; D017785:Photons; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
chemical_list: D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1