1. ^*Dermatology and Medical Service, Veterans Affairs Medical Center, San Francisco, California, USA
2. ^†Departments of Dermatology and Medicine, University of California, San Francisco, California, USA
3. ^‡Department of Dermatology and Allergology, Friedrich-Schiller-University, Jena, Germany

Correspondence: Joachim W. Fluhr, MD, Dermatology Service (190), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, California 94121, USA. Email: fluhr@derma.uni-jena.de

Received 8 March 2005; Revised 6 July 2005; Accepted 14 July 2005; Published online 15 November 2005.

Abstract

In neonatal rat stratum corneum (SC), pH declines from pH 6.8 at birth to adult levels (pH 5.0–5.5) over 5–6 d. Liver X receptor (LXR) activators stimulate keratinocyte differentiation, improve permeability barrier homeostasis, and accelerate the in utero development of the SC. In this manuscript we determined the effect of LXR activators on SC acidification in the neonatal period and whether these activators correct the functional abnormalities in permeability barrier homeostasis and SC integrity/cohesion. Formation of the acid SC-buffer system was accelerated by topically applying the LXR activator, 22(R)-hydroxycholesterol, and non-oxysterol activators of LXR, TO-901317, and GW-3965. A sterol which does not activate LXR had no effect. LXR activation increased secretory phospholipase A₂ (sPLA₂) activity and conversely, inhibition of sPLA₂ activity prevented the LXR induced increase in SC acidification, suggesting that increasing sPLA₂ accounts in part, for the LXR stimulation of acidification. LXR activation resulted in an improvement in permeability barrier homeostasis, associated with an increased maturation of lamellar membranes attributable to an increased -glucocerebrosidase activity. SC integrity cohesion also normalized in LXR-activator-treated animals and was associated with an increase in corneodesmosomes and in desmoglein 1 expression. These results demonstrate that LXR activators stimulate the formation of an acidic SC and improve both permeability barrier homeostasis and SC integrity/cohesion.