Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.

Holleran, Walter M.; Takagi, Ibuki; Menon, Gopinathan K.; Legler, I Gunter; Feingold, Kenneth R.; Elias, Peter M.

doi:10.1172/jci116374

Cited by 245 publications

(209 citation statements)

References 46 publications

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“…Previous studies demonstrate that initial lipid processing normally occurs in extracellular domains (3), and that it is this initial lipid processing step, at the SG-SC interface and in the lower SC, that is disturbed in: 1) neutral buffer-exposed skin, 2) NHE1 Ϫ/Ϫ mice, and 3) normal mice treated with the specific NHE1 inhibitor, HOE694. This view is supported by insights from other knockout models/ diseases, which also reveal the SG-SC interface to be an area of intense enzymatic lipid processing activity (5)(6)(7)32). Here we show with FLIM that this compartment is already acidified in normal skin, contrary to the conventional view of the pH gradient obtained with flat electrodes, which would predict this compartment to be neutral.…”

Section: Nhe1 Regulates Epidermal Ph and Barrier Functionmentioning

confidence: 81%

NHE1 Regulates the Stratum Corneum Permeability Barrier Homeostasis

Behne

Meyer

Hanson

et al. 2002

Journal of Biological Chemistry

190

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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.

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Section: Nhe1 Regulates Epidermal Ph and Barrier Functionmentioning

confidence: 81%

NHE1 Regulates the Stratum Corneum Permeability Barrier Homeostasis

Behne

Meyer

Hanson

et al. 2002

Journal of Biological Chemistry

190

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“…Moreover, given the large hydrophobic binding pockets in CD1d, the presence of CD1d on the outer layers of epidermis in psoriatic plaques opens up the possibility that various glycolipids present in the stratum corneum could play a role in triggering a response by NK-T cells or other T cell subsets capable of recognizing such glycolipids in the context of CD1d. During epidermal differentiation keratinocytes produce different amounts and types of various glycolipids, including glucosylceramides (49). Alterations in these glycolipids in the stratum corneum can have a significant impact on the barrier function of skin.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CD1d by Keratinocytes in Psoriasis and CD1d-Dependent IFN-γ Production by NK-T Cells

Bonish

Jullien

Dutronc

et al. 2000

The Journal of Immunology

205

187

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The MHC class I-like protein CD1d is a nonpolymorphic molecule that plays a central role in development and activation of a subset of T cells that coexpress receptors used by NK cells (NK-T cells). Recently, T cells bearing NK receptors were identified in acute and chronic lesions of psoriasis. To determine whether NK-T cells could interact with epidermal cells, we examined the pattern of expression of CD1d in normal skin, psoriasis, and related skin disorders, using a panel of CD1d-specific mAbs. CD1d was expressed by keratinocytes in normal skin, although expression was at a relatively low level and was generally confined to upper level keratinocytes immediately beneath the lipid-rich stratum corneum. In contrast, there was overexpression of CD1d in chronic, active psoriatic plaques. CD1d could be rapidly induced on keratinocytes in normal skin by physical trauma that disrupted barrier function or by application of a potent contact-sensitizing agent. Keratinocytes displayed enhanced CD1d following exposure to IFN-γ. Combining CD1d-positive keratinocytes with human NK-T cell clones resulted in clustering of NK-T cells, and while no significant proliferation ensued, NK-T cells became activated to produce large amounts of IFN-γ. We conclude that CD1d can be expressed in a functionally active form by keratinocytes and is up-regulated in psoriasis and other inflammatory dermatoses. The ability of IFN-γ to enhance keratinocyte CD1d expression and the subsequent ability of CD1d-positive keratinocytes to activate NK-T cells to produce IFN-γ, could provide a mechanism that contributes to the pathogenesis of psoriasis and other skin disorders.

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“…Similarly, we found that loss of ABCA12 activity did not significantly affect skin-free fatty acids levels, including that of linoleic acid, which indicates that the loss of the linoleic ceramide esters was not secondary to insufficient cellular linoleate supplies. Although it is formally possible that ABCA12 could play a role in transporting ␤-glucocerebrosidase rather than its substrate lipids, studies in animals either lacking the enzyme in the skin or treated with an enzyme inhibitor have reported no disruption of the epidermal lamellar body structure (38,39). Additionally, loss of ␤-glucocerebrosidase, or its activator Saposin-C caused a different spectrum of ceramide and glucosylceramide alterations in the skin than those we report here in the Abca12 Ϫ/Ϫ mice (40,41).…”

Section: That Their Abca12mentioning

confidence: 99%

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

Zuo

Zhuang

Han

et al. 2008

Journal of Biological Chemistry

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Harlequin ichthyosis is a congenital scaling syndrome of the skin in which affected infants have epidermal hyperkeratosis and a defective permeability barrier. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis, but the molecular function of the protein is unknown. To investigate the activity of ABCA12, we generated Abca12 null mice and analyzed the impact on skin function and lipid content. Abca12 ؊/؊ mice are born with a thickened epidermis and die shortly after birth, as water rapidly evaporates from their skin. In vivo skin proliferation measurements suggest a lack of desquamation of the skin cells, rather than enhanced proliferation of basal layer keratinocytes, accounts for the 5-fold thickening of the Abca12 ؊/؊ stratum corneum. Electron microscopy revealed a loss of the lamellar permeability barrier in Abca12 ؊/؊ skin. This was associated with a profound reduction in skin linoleic esters of long-chain -hydroxyceramides and a corresponding increase in their glucosyl ceramide precursors. Because -hydroxyceramides are required for the barrier function of the skin, these results establish that ABCA12 activity is required for the generation of longchain ceramide esters that are essential for the development of normal skin structure and function. Harlequin ichthyosis (HI)2 is the most severe of the congenital, autosomal ichthyoses with affected infants developing large, hard, plate-like scales over all of their epidermal surfaces. Abnormal temperature regulation, enhanced water loss, and bacterial super-infections develop as a consequence of defects in the barrier functions of the skin, making survival through the neonatal period difficult. In recent years, several groups have linked HI, as well as less severe forms of ichthyosis, to mutations in the gene encoding a member of the ABCA family of transporters, ABCA12 (1-7). The A class of ABC transporters consists of at least eleven transporters in humans and mice, several of which are known to play critical roles in human disease. ABCA1, the best studied of the proteins, is causally linked to Tangier disease and is associated with defective phospholipid and cholesterol transport from intracellular lipid stores to the major amphipathic helical apoprotein of high density lipoprotein, apolipoprotein A-1 (8 -11). ABCA3 mutations cause a form of neonatal respiratory failure that arises from a failure to transport pulmonary phospholipids comprising surfactant from their storage site in the lamellar bodies of alveolar type II cells to the alveolar space (12)(13)(14). This transport process, like the one involving ABCA1, appears to depend on the lipidation of an acceptor amphipathic helical protein, surfactant protein B (15, 16). ABCA4 causes Stargadt macular degeneration and visual loss that is associated with a defect in the transport of phosphatidylethanolamine-retinylidene adducts out of retinal pigment epithelial cells (17)(18)(19). The role of any acceptor proteins in this process is unknown. T...

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Processing of epidermal glucosylceramides is required for optimal mammalian cutaneous permeability barrier function.

Cited by 245 publications

References 46 publications

NHE1 Regulates the Stratum Corneum Permeability Barrier Homeostasis

NHE1 Regulates the Stratum Corneum Permeability Barrier Homeostasis

Overexpression of CD1d by Keratinocytes in Psoriasis and CD1d-Dependent IFN-γ Production by NK-T Cells

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

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