NHE1 Regulates the Stratum Corneum Permeability Barrier Homeostasis

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.

Skin barrier structure and function and their relationship to pruritus in end-stage renal disease

“…Elevated skin surface pH has been demonstrated previously in ESRD [15], however, the exact mechanisms are unknown. A defect in the non-energy-dependent sodium-proton exchanger (NHE 1) in keratinocytes could be causative [39]; however, this requires further investigation. Elevated SC pH induces activation of serine proteases which in turn leads to abnormal barrier function and SC integrity [40].…”

Postnatal Requirement of the Epithelial Sodium Channel for Maintenance of Epidermal Barrier Function

“…A number of mechanisms have been proposed for the generation of stratum corneum acidity, such as H ϩ generated by Na/H exchanger in the stratum granulosum (54) and catabolic processes within the stratum corneum that generate acidic endproducts. Intrinsic processes are (i) the breakdown of proteins such as filaggrin resulting in urocanic acid production (55) and (ii) the hydrolysis of lipids through specific phospholipases to yield free fatty acids (55,56).…”

NHE1 expression at wound margins increases time‐dependently during physiological healing

“…On the other hand, NHE1 is the pivotal player in extracellular acidification within the epidermis. 3 In vivo studies, for example on mice, are needed to make a decision on whether to increase or decrease pH e on surfaces of acute and chronic wounds. However, as we have shown recently that low pH e inhibits proliferation and centripetal migration of keratinocytes at the wound margins, 9 we speculate that a rather high pH e might contribute to increased movement of the migration front, thereby fostering wound closure.…”