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• W1965892292 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 β-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. 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 β-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. 22(R)-hydroxycholesterol acid sphingmyelinase bromphenacylbromide dimethyl sulfoxide desmoglein 1 β-glucocerebrosidase Liver X receptor activators sodium/hydrogen antiporter-1 Stratum corneum stratum granulosum secretory phospholipase A2 transepidermal water loss That the surface of the skin is acidic (acidic stratum corneum (SC)-buffer system) has been recognized for decades (Heuss, 1892Heuss E. Die Reaktion des Schweisses beim gesunden Menschen.Monatschr Prakt Dermatol. 1892; 14: 343-359Google Scholar; Schade, 1928Schade H.M. Zur physikalischen Chemie der Hautoberfl äche.Archiv Dermatol Syphil. 1928; 154: 690-716Crossref Scopus (19) Google Scholar; Marchionini and Hausknecht, 1938Marchionini A. Hausknecht W. Säuremantel der Haut und Bakterienabwehr.Klin Wochenschr. 1938; 17: 663-666Crossref Scopus (32) Google Scholar; Blank, 1939Blank I.A. Measurement of pH of the skin surface. II. pH of the exposed surfaces of adults with no apparent skin lesions.J Invest Dermatol. 1939; 2: 75-79Crossref Google Scholar; Bernstein and Hermann, 1942Bernstein E.T. Hermann F. The acidity on the surface of the skin.NY State J Med. 1942; 42: 436-442Google Scholar; Draize, 1942Draize J.H. The determination of the pH of the skin of man and common laboratory animals.J Invest Dermatol. 1942; 5: 77-85Crossref Google Scholar; Arbenz, 1952Arbenz H. Untersuchungen über die pH-Werte der normalen Hautoberfl äche.Dermatologica. 1952; 105: 333-354Crossref PubMed Scopus (10) Google Scholar; Behrendt and Green, 1958Behrendt H. Green M. Skin pH pattern in the newborn infant.J Dis Child. 1958; 95: 35-41PubMed Google Scholar; Beare et al., 1960Beare J. Cheeseman E. Gailey A. Neill D. Merrett J. The effect of age on the pH of the skin surface in the first week of life.Br J Dermatol. 1960; 72: 62-66Crossref PubMed Scopus (12) Google Scholar; Jolly, 1960Jolly Jr, H.W. pH determinations of the skin: Readings under normal and abnormal conditins.J Invest Dermatol. 1960: 305-308Google Scholar; Baden and Pathak, 1967Baden H.P. Pathak M.A. The metabolism and function of urocanic acid in skin.J Invest Dermatol. 1967; 48: 11-17Abstract Full Text PDF PubMed Scopus (105) Google Scholar; Tippelt, 1969Tippelt H. Zur Hautoberfl ächen-pH-Mesung und Alkaliresistenzprobe bei Hautgesunden und Ichthyosis vulgaris-Kranken.Dermatologica. 1969; 139: 201-210Crossref PubMed Google Scholar; Braun-Falco and Korting, 1986Braun-Falco O. Korting H.C. Normal pH value of human skin.Hautarzt. 1986; 37: 126-129PubMed Google Scholar; Zlotogorski, 1987Zlotogorski A. Distribution of skin surface pH on the forehead and cheek of adults.Arch Dermatol Res. 1987; 279: 398-401Crossref PubMed Scopus (129) Google Scholar; Korting et al., 1990Korting H.C. Hubner K. Greiner K. Hamm G. Braun-Falco O. Differences in the skin surface pH and bacterial microflora due to the long-term application of synthetic detergent preparations of pH 5.5 and pH 7.0. Results of a crossover trial in healthy volunteers.Acta Derm Venereol. 1990; 70: 429-431PubMed Google Scholar; Seidenari and Giusti, 1995Seidenari S. Giusti G. Objective assessment of the skin of children affected by atopic dermatitis: A study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin.Acta Derm Venereol. 1995; 75: 429-433PubMed Google Scholar; Berardesca et al., 1998Berardesca E. Pirot F. Singh M. Maibach H. Differences in stratum corneum pH gradient when comparing white Caucasian and black African-American skin.Br J Dermatol. 1998; 139: 855-857Crossref PubMed Scopus (80) Google Scholar; Yosipovitch et al., 1998Yosipovitch G. Xiong G.L. Haus E. Sackett-Lundeen L. Ashkenazi I. Maibach H.I. Time-dependent variations of the skin barrier function in humans: Transepidermal water loss, stratum corneum hydration, skin surface pH, and skin temperature.J Invest Dermatol. 1998; 110: 20-23Crossref PubMed Scopus (210) Google Scholar; Eberlein-Konig et al., 2000Eberlein-Konig B. Schafer T. Huss-Marp J. et al.Skin surface pH, stratum corneum hydration, trans-epidermal water loss and skin roughness related to atopic eczema and skin dryness in a population of primary school children.Acta Derm Venereol. 2000; 80: 188-191Crossref PubMed Scopus (159) Google Scholar; Fluhr et al., 2000Fluhr J.W. Pfisterer S. Gloor M. Direct comparison of skin physiology in children and adults with bioengineering methods.Pediatr Dermatol. 2000; 17: 436-439Crossref PubMed Scopus (77) Google Scholar), but the mechanisms that account for its acidification are still not completely understood. It is postulated that exogenous pathways (originating outside the epidermis), such as microbial metabolites (Di Marzio et al., 1999Di Marzio L. Cinque B. De Simone C. Cifone M.G. Effect of the lactic acid bacterium Streptococcus thermophilus on ceramide levels in human keratinocytes in vitro and stratum corneum in vivo.J Invest Dermatol. 1999; 113: 98-106Crossref PubMed Scopus (42) Google Scholar), free fatty acids of pilosebaceous origin (Puhvel et al., 1975Puhvel S.M. Reisner R.M. Sakamoto M. Analysis of lipid composition of isolated human sebaceous gland homogenates after incubation with cutaneous bacteria. Thin-layer chromatography.J Invest Dermatol. 1975; 64: 406-411Crossref PubMed Scopus (45) Google Scholar; Bibel et al., 1989Bibel D.J. Miller S.J. Brown B.E. Pandey B.B. Elias P.M. Shinefield H.R. Aly R. Antimicrobial activity of stratum corneum lipids from normal and essential fatty acid-deficient mice.J Invest Dermatol. 1989; 92: 632-638Abstract Full Text PDF PubMed Google Scholar), and eccrine gland-derived products (Ament et al., 1997Ament W. Huizenga J.R. Mook G.A. Gips C.H. Verkerke G.J. Lactate and ammonia concentration in blood and sweat during incremental cycle ergometer exercise.Int J Sports Med. 1997; 18: 35-39Crossref PubMed Scopus (64) Google Scholar), such as lactic acid (Thueson et al., 1998Thueson D.O. Chan E.K. Oechsli L.M. Hahn G.S. The roles of pH and concentration in lactic acid-induced stimulation of epidermal turnover.Dermatol Surg. 1998; 24: 641-645Crossref PubMed Scopus (28) Google Scholar), contribute to SC acidification. Additionally, recent studies have shown that endogenous pathways are also important for SC acidification (Fluhr et al., 2001aFluhr J.W. Kao J. Jain M. Ahn S.K. Feingold K.R. Elias P.M. Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity.J Invest Dermatol. 2001; 117: 44-51Crossref PubMed Google Scholar,Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar; Behne et al., 2002Behne M.J. Meyer J. Hanson K.M. et al.NHE1 regulates the stratum corneum permeability barrier homeostasis: Microenvironment acidification assessed with FLIM.J Biol Chem. 2002; 277: 47399-47406Crossref PubMed Scopus (164) Google Scholar). Generation of cis-urocanic acid from histidine (Schwarz et al., 1986Schwarz W. Langer K. Schell H. Schonberger A. Distribution of urocanic acid in human stratum corneum.Photodermatology. 1986; 3: 239-240PubMed Google Scholar; Krien and Kermici, 2000Krien P.M. Kermici M. Evidence for the existence of a self-regulated enzymatic process within the human stratum corneum—an unexpected role for urocanic acid.J Invest Dermatol. 2000; 115: 414-420Crossref PubMed Scopus (119) Google Scholar), free fatty acid generation from phospholipid hydrolysis catalyzed by secretory phospholipase A2 (sPLA2) (Mao-Qiang et al., 1996Mao-Qiang M. Jain M. Feingold K.R. Elias P.M. Secretory phospholipase A2 activity is required for permeability barrier homeostasis.J Invest Dermatol. 1996; 106: 57-63Crossref PubMed Scopus (94) Google Scholar; Fluhr et al., 2001aFluhr J.W. Kao J. Jain M. Ahn S.K. Feingold K.R. Elias P.M. Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity.J Invest Dermatol. 2001; 117: 44-51Crossref PubMed Google Scholar,Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar), and a sodium/proton pump antiporter, sodium/hydrogen antiporter-1 (NHE1) (Behne et al., 2002Behne M.J. Meyer J. Hanson K.M. et al.NHE1 regulates the stratum corneum permeability barrier homeostasis: Microenvironment acidification assessed with FLIM.J Biol Chem. 2002; 277: 47399-47406Crossref PubMed Scopus (164) Google Scholar,Behne et al., 2003Behne M.J. Barry N.P. Hanson K.M. et al.Neonatal development of the stratum corneum pH gradient: Localization and mechanisms leading to emergence of optimal barrier function.J Invest Dermatol. 2003; 120: 998-1006Abstract Full Text Full Text PDF PubMed Google Scholar; Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar), have all been shown to play a role in SC acidification. Both a fully developed cornified envelope (Hardman et al., 1998Hardman M.J. Sisi P. Banbury D.N. Byrne C. Patterned acquisition of skin barrier function during development.Development. 1998; 125: 1541-1552Crossref PubMed Google Scholar; Komuves et al., 1998Komuves L.G. Hanley K. Jiang Y. Elias P.M. Williams M.L. Feingold K.R. Ligands and activators of nuclear hormone receptors regulate epidermal differentiation during fetal rat skin development.J Invest Dermatol. 1998; 111: 429-433Crossref PubMed Scopus (90) Google Scholar; Lee et al., 1999Lee S.C. Lee J.B. Kook J.P. Seo J.J. Nam K.I. Park S.S. Kim Y.P. Expression of differentiation markers during fetal skin development in humans: Immunohistochemical studies on the precursor proteins forming the cornified cell envelope.J Invest Dermatol. 1999; 112: 882-886Crossref PubMed Scopus (29) Google Scholar) and abundant extracellular lamellar membranes (Hanley et al., 1997Hanley K. Devaskar U.P. Hicks S.J. et al.Hypothyroidism delays fetal stratum corneum development in mice.Pediatr Res. 1997; 42: 610-614Crossref PubMed Scopus (26) Google Scholar; Williams et al., 1998Williams M.L. Hanley K. Elias P.M. Feingold K.R. Ontogeny of the epidermal permeability barrier.J Investig Dermatol Symp Proc. 1998; 3: 75-79Abstract Full Text PDF PubMed Scopus (58) Google Scholar; Hanley et al., 1999Hanley K. Komuves L.G. Bass N.M. et al.Fetal epidermal differentiation and barrier development in vivo is accelerated by nuclear hormone receptor activators.J Invest Dermatol. 1999; 113: 788-795Crossref PubMed Scopus (82) Google Scholar) are generated in the SC late in gestation. Hence prior to birth, the fetus develops a cutaneous permeability barrier sufficient for survival in a terrestrial environment. But skin surface pH is neutral at birth both in humans and in rodents (Behrendt and Green, 1958Behrendt H. Green M. Skin pH pattern in the newborn infant.J Dis Child. 1958; 95: 35-41PubMed Google Scholar; Visscher et al., 2000Visscher M.O. Chatterjee R. Munson K.A. Pickens W.L. Hoath S.B. Changes in diapered and nondiapered infant skin over the first month of life.Pediatr Dermatol. 2000; 17: 45-51Crossref PubMed Scopus (131) Google Scholar; Yosipovitch et al., 2000Yosipovitch G. Maayan-Metzger A. Merlob P. Sirota L. Skin barrier properties in different body areas in neonates.Pediatrics. 2000; 106: 105-108Crossref PubMed Scopus (154) Google Scholar; Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). In humans it takes several weeks to months before the SC is fully acidified whereas in the neonatal rat the SC attains normal adult pH levels over the first postnatal week (Behrendt and Green, 1958Behrendt H. Green M. Skin pH pattern in the newborn infant.J Dis Child. 1958; 95: 35-41PubMed Google Scholar; Visscher et al., 2000Visscher M.O. Chatterjee R. Munson K.A. Pickens W.L. Hoath S.B. Changes in diapered and nondiapered infant skin over the first month of life.Pediatr Dermatol. 2000; 17: 45-51Crossref PubMed Scopus (131) Google Scholar; Yosipovitch et al., 2000Yosipovitch G. Maayan-Metzger A. Merlob P. Sirota L. Skin barrier properties in different body areas in neonates.Pediatrics. 2000; 106: 105-108Crossref PubMed Scopus (154) Google Scholar; Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Recent studies by our laboratory have shown in rodents that sPLA2 activity is low at birth but increases progressively after birth (Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Moreover, inhibition of sPLA2 activity delays postnatal SC acidification. The NHE1 antiporter is expressed at birth and inhibition of this transporter also delays SC acidification in the neonatal period (Behne et al., 2003Behne M.J. Barry N.P. Hanson K.M. et al.Neonatal development of the stratum corneum pH gradient: Localization and mechanisms leading to emergence of optimal barrier function.J Invest Dermatol. 2003; 120: 998-1006Abstract Full Text Full Text PDF PubMed Google Scholar; Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Conversely, neither microbial colonization nor urocanic acid appears to play a key role in neonatal acidification (Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Thus, the postnatal acidification of the SC can be attributed, at least in part, to sPLA2 and NHE1 (Behne et al., 2003Behne M.J. Barry N.P. Hanson K.M. et al.Neonatal development of the stratum corneum pH gradient: Localization and mechanisms leading to emergence of optimal barrier function.J Invest Dermatol. 2003; 120: 998-1006Abstract Full Text Full Text PDF PubMed Google Scholar; Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar) and sPLA2 and NHE1 have been identified to be key sources of endogenous SC acidification. Traditionally the major function of the acid SC-buffer system has been assumed to be antimicrobial (Aly et al., 1975Aly R. Maibach H.I. Rahman R. Shinefield H.R. Mandel A.D. Correlation of human in vivo and in vitro cutaneous antimicrobial factors.J Infect Dis. 1975; 131: 579-583Crossref PubMed Scopus (48) Google Scholar; Hartmann, 1983Hartmann A.A. Effect of occlusion on resident flora, skin-moisture and skin-pH.Arch Dermatol Res. 1983; 275: 251-254PubMed Google Scholar; Bibel et al., 1989Bibel D.J. Miller S.J. Brown B.E. Pandey B.B. Elias P.M. Shinefield H.R. Aly R. Antimicrobial activity of stratum corneum lipids from normal and essential fatty acid-deficient mice.J Invest Dermatol. 1989; 92: 632-638Abstract Full Text PDF PubMed Google Scholar). But recent studies have demonstrated abnormalities in the function of the SC in the neonatal period, which are because of the lack of an acidic SC at birth (Fluhr et al., 2004aFluhr J.W. Behne M.J. Brown B.E. et al.Stratum corneum acidification in neonatal skin: Secretory phospholipase A2 and the sodium/hydrogen antiporter-1 acidify neonatal rat stratum corneum.J Invest Dermatol. 2004; 122: 320-329Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Specifically, although basal permeability barrier function is competent in neonates, the recovery of permeability barrier function following acute barrier disruption is delayed (Fluhr et al., 2004bFluhr J.W. Mao-Qiang M. Brown B.E. et al.Functional consequences of a neutral pH in neonatal rat stratum corneum.J Invest Dermatol. 2004; 123: 140-151Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). The delay in barrier recovery was attributed to incompletely processed lamellar membranes in the SC because of a decrease in the activity of a key enzyme for lipid processing during SC maturation; β-glucocerebrosidase, an enzyme whose optimal activity is at an acidic pH. Both the abnormality in permeability barrier homeostasis and the structural abnormality of the lamellar membranes could be corrected by topical treatment with an acidic buffer, which normalized β-glucocerebrosidase activity (Fluhr et al., 2004bFluhr J.W. Mao-Qiang M. Brown B.E. et al.Functional consequences of a neutral pH in neonatal rat stratum corneum.J Invest Dermatol. 2004; 123: 140-151Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). In addition to the abnormality in permeability homeostasis, a decrease in SC integrity also was seen in newborn rats. The decrease in SC integrity was attributed to a decrease in the density of corneodesmosomes (CD), with an associated decrease in desmoglein 1 and corneodesmosin protein expression in the neonatal SC (Fluhr et al., 2004bFluhr J.W. Mao-Qiang M. Brown B.E. et al.Functional consequences of a neutral pH in neonatal rat stratum corneum.J Invest Dermatol. 2004; 123: 140-151Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). CD are key structures for SC cohesion and desmoglein 1 is one of the major proteins of CD. Alteration in CD density correlate with changes in SC integrity and cohesion. Topical treatment with an acidic buffer again increased the number of CD and restored SC integrity to normal (Fluhr et al., 2004bFluhr J.W. Mao-Qiang M. Brown B.E. et al.Functional consequences of a neutral pH in neonatal rat stratum corneum.J Invest Dermatol. 2004; 123: 140-151Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). Thus, the delay in acidification of neonatal skin results in functional abnormalities that could have adverse clinical consequences for the newborn. Liver X receptor (LXR) are members of the nuclear hormone receptor superfamily, which form heterodimers with RXR, in order to activate gene transcription. Two genes, α and β, encode the LXR paralogues. LXRα is expressed predominately in the liver and to a lesser extent in the kidney, spleen, adrenal gland, and the small intestine (Willy et al., 1995Willy P.J. Umesono K. Ong E.S. Evans R.M. Heyman R.A. Mangelsdorf D.J. LXR, a nuclear receptor that defines a distinct retinoid response pathway.Genes Dev. 1995; 9: 1033-1045Crossref PubMed Scopus (851) Google Scholar), whereas LXRβ is ubiquitously expressed (Song et al., 1995Song C. Hiipakka R.A. Kokontis J.M. Liao S. Ubiquitous receptor: Structures, immunocytochemical localization, and modulation of gene activation by receptors for retinoic acids and thyroid hormones.Ann NY Acad Sci. 1995; 761: 38-49Crossref PubMed Scopus (43) Google Scholar). Our laboratory has shown that both LXRα and LXRβ are present in cultured human keratinocytes and in fetal rat epidermis (Hanley et al., 1999Hanley K. Komuves L.G. Bass N.M. et al.Fetal epidermal differentiation and barrier development in vivo is accelerated by nuclear hormone receptor activators.J Invest Dermatol. 1999; 113: 788-795Crossref PubMed Scopus (82) Google Scholar,Hanley et al., 2000Hanley K. Komuves L.G. Ng D.C. et al.Farnesol stimulates differentiation in epidermal keratinocytes via PPARalpha.J Biol Chem. 2000; 275: 11484-11491Crossref PubMed Scopus (93) Google Scholar). LXRα and LXRβ are now recognized to bind oxysterols, including 22(R)-hydroxycholesterol (22(R)-Chol), 24(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol. Activation of LXR regulates important pathways in cholesterol, fatty acid, and bile acid metabolism. Recently, we demonstrated that topical application of oxysterols to murine epidermis and the addition of oxysterols to human keratinocyte cultures stimulate keratinocyte differentiation (Fowler et al., 2003Fowler A.J. Sheu M.Y. Schmuth M. et al.Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: Liver-X-receptor-specific inhibition of inflammation and primary cytokine production.J Invest Dermatol. 2003; 120: 246-255Crossref PubMed Scopus (196) Google Scholar; Schmuth et al., 2004Schmuth M. Elias P.M. Hanley K. et al.The effect of LXR activators on AP-1 proteins in keratinocytes.J Invest Dermatol. 2004; 123: 41-48Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,Schmuth et al., 2005Schmuth M. Bikle D.D. Willson T.M. Mangelsdorf D.J. Elias P.M. Feingold K.R. Pro-differentiating effects of oxysterols in keratinocytes.Exp Dermatol. 2005; 14: 154-155Crossref Google Scholar). In addition, topical oxysterol treatment of normal adult animals improves permeability barrier homeostasis following acute barrier disruption (Komuves et al., 2002Komuves L.G. Schmuth M. Fowler A.J. et al.Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis.J Invest Dermatol. 2002; 118: 25-34Crossref PubMed Scopus (78) Google Scholar). Furthermore, in an animal model of epidermal hyperplasia, oxysterol treatment restored epidermal morphology towards normal by both inhibiting proliferation and stimulating differentiation (Komuves et al., 2002Komuves L.G. Schmuth M. Fowler A.J. et al.Oxysterol stimulation of epidermal differentiation is mediated by liver X receptor-beta in murine epidermis.J Invest Dermatol. 2002; 118: 25-34Crossref PubMed Scopus (78) Google Scholar). Finally, and of particular pertinence to this manuscript, oxysterols also accelerate the formation of the epidermal permeability barrier and stimulate differentiation during fetal development (Hanley et al., 1999Hanley K. Komuves L.G. Bass N.M. et al.Fetal epidermal differentiation and barrier development in vivo is accelerated by nuclear hormone receptor activators.J Invest Dermatol. 1999; 113: 788-795Crossref PubMed Scopus (82) Google Scholar,Hanley et al., 2000Hanley K. Komuves L.G. Ng D.C. et al.Farnesol stimulates differentiation in epidermal keratinocytes via PPARalpha.J Biol Chem. 2000; 275: 11484-11491Crossref PubMed Scopus (93) Google Scholar). Thus, activation of LXR improves epidermal function in a variety of experimental models. We therefore hypothesized that treatment of neonatal rat skin with LXR activators could stimulate acidification and normalize the previously described abnormalities in cutaneous function that occur in the neonatal epidermis. In separate experiments, topical treatment of newborn mice for 3 d with three chemically unrelated LXR activators, an oxysterol, 22(R)-Chol, and two non-oxysterol pharmacologic activators of LXR, TO-901317 and GW 3965, stimulated the acidification of neonatal skin (Figure 1). In contrast, topical treatment with cholesterol, a sterol compound that does not activate LXR, did not stimulate acidification. Similar to studies in adult rodents, topical treatment with LXR activators stimulated the expression of loricrin, involucrin, and filaggrin in the newborn rats treated with 22(R)-Chol (data not shown). We next determined whether topical treatment with LXR activators would improve the abnormality in permeability barrier homeostasis that occurs in newborn rodents. As shown in Figure 2, topical treatment with 22(R)-Chol accelerated barrier recovery following acute disruption of the barrier by tape stripping. The control group in Figure 2 shows a slight delay in barrier recovery compared with untreated neonatal rat (Fluhr et al., 2004bFluhr J.W. Mao-Qiang M. Brown B.E. et al.Functional consequences of a neutral pH in neonatal rat stratum corneum.J Invest Dermatol. 2004; 123: 140-151Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). The control group was treated with the solvent (acetone) for 3 d, which may partially explain the delay in barrier recovery. The improvement in barrier homeostasis was associated with a normalization of lamellar membrane maturation in the SC on qualitative analysis of the electron micrographs (Figure 3b vs a). Vehicle-treated neonates demonstrated extracellular lamellar membranes that were immature i.e. incompletely processed (Figure 3a), whereas in oxysterol-treated animals the lamellar membranes were more mature in appearance (i.e., completely processed) (Figure 3b). LXR-treated neonatal membrane structures were identical, i.e., as mature, as membranes seen in day 5 neonatal rat epidermis (Figure 4a).Figure 3Liver X receptor (LXR) activators accelerate maturation of extracellular lamellar membranes in neonatal rat stratum corneum (SC). Neonates were treated twice daily with either 22(R)-hydroxycholesterol or vehicle for 3 d as described in ‘Methods.’ Three hours after barrier disruption by tape stripping samples were obtained and prepared for EM analysis as described in ‘Methods’. Although incompletely processed “immature” membranes predominate in vehicle-treated animals (A, arrows), in the LXR-treated animals membrane structure was normalized (B, arrows). (A, B) Ruthenium tetroxide post-fixation. (Scale bar=0.25 μm).View Large Image Figure ViewerDownload (PPT)Figure 4Liver X receptor (LXR) activators normalize corneodesmosome density and size. (A, B) Differences in membrane maturation (arrows) of untreated newborns (B) versus 5 d-old animals (A). (C, D) Neonates were treated twice daily with either 22(R)-hydroxycholesterol or vehicle for 3 d as described in ‘Methods.’ LXR activators both increase CD density and the size of individual CD (arrowheads D vs C). (A, B) R" @default.
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