stratum corneum ph in atopic dermatitis

Am J Clin Dermatol 2004; 5 (4): 217-223LEADING ARTICLE 1175-0561/04/0004-0217/$31.00/0

© 2004 Adis Data Information BV. All rights reserved.

Stratum Corneum pH in Atopic DermatitisImpact on Skin Barrier Function and Colonization with Staphylococcus Aureus

Frank Rippke,1 Volker Schreiner,1 Thomas Doering1 and Howard I. Maibach2

1 Beiersdorf AG, Hamburg, Germany2 Department of Dermatology, University of California San Francisco Medical Center, San Francisco, California, USA

Recent studies have provided new insights into the occurrence, causes, and pathogenetic consequences ofAbstractchanges in the skin pH in atopic dermatitis, particularly with respect to skin barrier function and colonizationwith Staphylococcus aureus. Growing evidence suggests an impaired release of proton donors, such as aminoacids, urocanic acid, and lactic acid, to the stratum corneum in atopic dermatitis, as a result of reductions infilaggrin proteolysis and sweat secretion. In addition, an impaired formation of free fatty acids from sebaceouslipids and epidermal phospholipids seems to be involved. Because both lipid organization and lipid metabolismin the stratum corneum requires an acidic pH, these alterations might contribute to the disturbance of skin barrierfunction observed in atopic dermatitis. Furthermore, bacterial growth and virulence of S. aureus, as well asdefensive host mechanisms, have increasingly been delineated as pH dependent, giving rise to a new understand-ing of the pathophysiology underlying increased skin colonization seen in atopic dermatitis.

The main significance of pH in the stratum corneum has largely in the normally acidic stratum corneum, are the paramountclassically been considered in terms of a defense mechanism functions of the skin”.[2]

against pathogenic microorganisms. However, it also plays a The pH of the stratum corneum is influenced by numeroussignificant role in skin barrier homeostasis, affecting stratum factors:[1,4,5,7] endogenous factors include sweat and sebum secre-corneum desquamation[1-4] and controlling the postsecretory tion, as well as anatomical conditions; exogenous factors includeprocessing of lipid precursors degraded by enzymes with an acidic the effects of soaps or occlusion, as well as diseases such aspH optimum.[3] Non-occluded skin normally lies in the range of diabetes mellitus, irritant contact dermatitis, or atopic dermatitis. ItpH 4–6,[5] while the mean pH of the surface of the skin in the is likely that an altered pH is not only an epiphenomenon but also aforearm region of a healthy, adult, White male has been reported in meaningful etiological component. It has been concluded onlythe range of 5.4–5.9.[6] These physiologic values were long consid- recently “that the skin surface pH can be used as a more practicalered the ‘acid mantle’ of the skin, although it is also found in, and biophysical parameter to quantitatively assess the inflammatoryaffects, deeper compartments of the stratum corneum. Biological- skin than the redness of the skin”.[10]

ly, the acidic milieu of the stratum corneum is maintained by the Current clinical and experimental studies have investigated theproducts of exocrine secretion, such as fatty acids from sebum, and role of the pH of the stratum corneum and its significance to thelactic and amino acids from sweat, as well as by-products of barrier function of skin, as well as the pathogenesis of variouskeratinization (e.g. amino acids, urocanic acid, pyrrolidone car- dermatoses.[1,5,7] This review assesses the significance of altera-boxylic acid) and free fatty acids from the hydrolysis of epidermal tions in the corneal pH, specifically with regard to certain pathoge-phospholipids (reviewed by Rippke et al.,[1] Fluhr and Elias,[7] and netic factors in atopic dermatitis, a disease characterized for exam-Parra and Paye[5]). Moreover, membrane-located ion transporters ple by flexural eczema, xerosis, and itch associated with sweat-of the lamellar bodies might also contribute to stratum corneum ing.[11]

acidification.[8] Na+/H+ exchanger isoform 1, a Na+/H+ antiporter,has recently been shown to be required for the acidification of 1. Alterations of Skin pH and its Factors inextracellular microdomains within the lowermost stratum corne- Atopic Dermatitisum.[9] Currently, the acidic pH of the stratum corneum is thoughtto play a key role in skin biology,[1,3,7] and it has been proposed Initial evidence for an altered skin surface pH in atopic dermati-that “the cohort of defensive functions of the epidermis, residing tis was established in the 1950s. These data have been confirmed

218 Rippke et al.

Table I. Assessments of skin pH in patients with atopic dermatitis and healthy controls

Study Panel n Age pH value on volar forearm pH value on forehead (±(± SD) SD)

Sparavigna et al.[15] Healthy skin 141 3mo–11y 5.36 ± 0.50

Atopic dermatitis: 143

uninvolved skin 5.52 ± 0.64a

perilesional skin 5.92 ± 0.74a

lesional skin 5.90 ± 0.76a

Eberlein-Konig et al.[13] Healthy skin 332 8–9y 5.12 ± 0.43

Atopic dermatitis 45 5.32 ± 0.43a

Seidenari and Giusti[14] Healthy skin 21 3–12y 4.86 ± 0.45 4.67 ± 0.39

Atopic dermatitis: 100

uninvolved skin 5.23 ± 0.74a 4.99 ± 0.66a,b

involved skin 5.54 ± 0.63a 5.68 ± 0.47a

Rugemer et al.[17] Healthy skin 31 4y 5.37 ± 0.67 4.83 ± 0.40

Atopic dermatitis: 70 4.7y

uninvolved skin 5.04 ± 0.42a 4.82 ± 0.54

involved skin 5.58 ± 0.65b 5.31 ± 0.39a,b

O’Goshi et al.[16] Healthy skin 40 8–42y 5.0 ± 0.5

Atopic dermatitis: 34 11–39y

uninvolved skin 5.9 ± 0.7a

involved skin 5.5 ± 0.6

Conti et al.[20] Healthy skin 60 22 ± 6y 5.10 ± 0.55 5.07 ± 0.47

Atopic dermatitis 38 Matched 5.51 ± 0.63a 5.40 ± 0.61a

a Significant vs healthy skin (p < 0.05)

b Significant vs uninvolved atopic dermatitis skin (p < 0.05)

mo = months; y = years.

in recent years by numerous large-scale systematic studies, em- study in children with atopic dermatitis revealed an overall shift toalkalinity with a significant difference on abdominal skin.[19]ploying planar glass electrodes for the assessment of pH (table I).

In addition to serum exudation of severely affected skin sites,Atopic dermatitis was diagnosed according to the criteria ofother factors can be considered as potential causes or conse-Hanifin and Rajka,[12] and current skin involvement assessed on aquences of these findings (table II).clinical basis. Although pH values recorded in a semihydrophobic

milieu such as the stratum corneum are relative, and should be1.1 Free Fatty Acids from Sebaceous Lipids

interpreted with caution,[5] it could be shown that the pH is higherin patients with atopic dermatitis than in healthy controls, even on A sebostasis-induced, absolute reduction of free fatty acids onuninvolved skin sites without lesions.[13-16] Furthermore, the in- the skin surface of patients with atopic dermatitis was reported increase could be correlated with the severity of dryness,[13] itch- 1974.[21] In contrast, other investigators[36] have reported a 6-fold

increase in the concentrations of free fatty acids in skin surfaceing[15] and eczematous skin symptoms.[14,15] Only one group oflipids in patients with atopic dermatitis compared with patientspatients with atopic dermatitis reported significantly lower pHwith acne. This may be due to an increased microbial lipolysis ofvalues on uninvolved forearm skin when compared with bothglycerides in spite of reduced sebaceous gland secretion in atopichealthy and involved skin.[17] However, they also confirmed adermatitis.[37]

significant elevation of the surface pH in lesional skin of theforehead and cubital fossa. Furthermore, these researchers have

1.2 Free Fatty Acids from Phospholipidsfound an overall positive correlation between pH values andseverity of atopic dermatitis, assessed using the composite SCOR- The generation of free fatty acids from phospholipids is thoughting of Atopic Dermatitis (SCORAD) index.[18] Another recent to play a crucial role in maintaining stratum corneum acidifica-

© 2004 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2004; 5 (4)

Stratum Corneum pH in Atopic Dermatitis 219

exertion by nearly a factor of three.[26] The reduced sweat secretionin atopic dermatitis can also be considered a reason for theobserved decrease in stratum corneum lactate values.[28]

Relatively recently, a sodium-coupled acid-base transportacross the basolateral membrane of the reabsorptive duct of thehuman eccrine sweat gland, most likely representing a Na+/H+

exchanger, was found to be involved in sweat acidification; reduc-tion of in vitro bath sodium concentrations led to marked decreasesof intracellular pH.[42] In vivo, significant relationships have beenreported between sweat (Na+ concentration) and pH in healthyhuman males[43] and altered sweat electrolyte concentrations withhighly increased sodium levels in children with atopic dermati-tis.[27] Although, to our knowledge, sweat pH values in atopicdermatitis have not yet been investigated, these findings also

Table II. Factors believed to be involved in pH alterations of atopic skin

Factor Function for Status in atopic Referencesacidic milieu dermatitis

Sebum secretion, Source of FFA Possibly reduced 21-24stratum corneumlipid maturation

Sweat secretion Source of AA, Reduced 25-27LA, protons

Filaggrin formation Source of AA, Reduced 20,28-34and/or degradation UCA

Odland body Source of Disturbed 35secretion protons

AA = amino acids; FFA = free fatty acids; LA = lactic acid; UCA = urocanicacid.

suggest a disturbance of sweat acidification.

tion.[38] A significant deficiency of free fatty acids in atopic1.4 Urocanic Aciddermatitis has been repeatedly reported for the stratum corneum

lipids.[22,23] However, both the phospholipid content of the atopicRecent findings suggest that urocanic acid, a product of filag-epidermis[39] and the activity of phospholipase A2[40] have been

grin proteolysis, may play a key role in maintenance of the acidicreported to be approximately twice as high in atopic skin as inpH of the stratum corneum.[44] According to the authors of thishealthy epidermis and, therefore, cannot be the reason for astudy, urocanic acid is produced from histidine by a self-regulatedputative deficiency of free fatty acids in the lipids of the stratumcontrol cycle, involving the pH-dependent activity of the enzymecorneum. Expression of the recently discovered sphingomyelinhistidase for the maintenance of moisture content and pH of thedeacylase, responsible for the release of fatty acids from sphingo-stratum corneum. It has long been known that urocanic acid ismyelin and glucosylceramides, is increased by 3- to 5-fold insignificantly reduced in atopic dermatitis.[28] More recent studiesatopic skin, depending on the severity of the disease.[41] On thehave confirmed this finding[32-34] and suggested a diminishedother hand, the same authors found a significant decrease in thehistidase activity in atopic skin, especially in patients aged >20activity of acid ceramidase, which hydrolizes ceramides intoyears, as histidine levels remained unchanged.[32,33] However,sphingosine and free fatty acids.[41] Therefore, the significance ofreduced filaggrin levels have also been reported for lesional andfree fatty acids to the altered pH of atopic skin remains inconclu-nonlesional skin in atopic dermatitis,[31] and future studies onsive.histidase knockout mice are required to establish a role for thispathway in stratum corneum acidification.1.3 Amino Acids, Lactic Acid, and Sweat Secretion

A marked reduction in free amino acids was reported as early as 1.5 Epidermal Lamellar Body Extrusion and Proton Pumpsthe 1970s in stratum corneum extracts of uninvolved skin, and was

The process of exocytosis of the lamellar bodies at the stratumfound to be even more pronounced in those with affected skin.[28]

granulosum-stratum corneum interface is another source of pro-This finding has since been confirmed for atopic xerosis[29,30] astons for stratum corneum acidification.[8] In atopic dermatitis, awell as atopic dermatitis;[29] in severe atopic dermatitis, an almostdelayed and incomplete secretion of lamellar bodies into thecomplete paucity of amino acids has been reported. Moreover,intercellular matrix can be observed.[35] Whether changes in thepatients with allergic rhinitis have also shown a significant reduc-activity of the Na+/H+ antiporters, located in the plasma membranetion in the levels of free amino acids.[29] However, in one study[20]

of epidermal keratinocytes,[9] also play a role in atopic dermatitisno changes in skin pH could be determined in patients withwould be an interesting topic for further studies.respiratory atopy compared with healthy controls. The amino acid

deficiency can be attributed both to a significant reduction of the Consequently, several factors in atopic dermatitis, both patho-epidermal protein filaggrin, which is formed as the most important genetic and therapeutically relevant, can be affected by theseprecursor of free amino acids of the stratum corneum during changes in skin surface pH. Besides genetic and immunologicterminal differentiation of the keratinocytes,[31] and to a reduced factors, skin dryness caused by, or coincident with, a disturbancesweat secretion in atopic dermatitis. Under thermal stress, sweat of skin barrier function and microbial colonization, especially withsecretion was reduced by 50–60% in patients with atopic dermati- Staphylococcus aureus in atopic dermatitis, is of great importance.tis compared with healthy controls[25] and reduced with physical These last two issues are discussed in detail in sections 2 and 3.


220 Rippke et al.

2. Impact on Skin Barrier Function corneum integrity, and cohesion.[58] The researchers consideredthis as support for their hypothesis that an increase in the stratum

The stratum corneum barrier function in atopic dermatitis iscorneum pH initiates cutaneous inflammation via activation and

subject to a number of characteristic functional and structuralrelease of primary cytokines, associated with pH-related serine

disturbances.[24] The skin is dry, shows an increased transepider-protease activation.

mal water loss as well as enhanced irritability, and is permeable toirritants and allergens. In addition to a reduction of the total 3. Impact on Staphylococcus Aureus Colonizationceramide fraction,[23,45,46] there is a striking shift in both free and

Massive colonization of the skin with S. aureus is considered tobound fatty acids from the polyunsaturated species, such as linole-be a major pathogenetic factor in atopic dermatitis because of theic acid, to the monounsaturated species, in particular, oleicability of this bacterial species to produce superantigens and toxinsacid.[39,47] At the ultrastructural level, there is evidence of dis-and, hence, trigger and sustain the inflammatory reaction.[59] Inturbed biosynthesis, excretion and maturation of the stratumrecent years, a number of interesting dependencies of bacterialcorneum lipids.[35] Many of these enzymatic processes are pHgrowth and virulence on the pH of the growth medium have beendependent; in particular, the enzymes responsible for the catabol-discovered. In general, growth of the strains studied was maximalism of sphingomyelin or glucosylceramides at the stratumat neutral pH[60,61] and markedly inhibited at values around pHgranulosum-stratum corneum interface (acidic sphingomyelinase5.[60-62] If the pH was kept constant by buffering, an additionaland glucocerebrosidase), which are most active at an acidicinhibition of growth could be observed with increasing lactatepH.[2,3,48] The activity of glucocerebrosidase in situ is ten timesconcentrations.[61] In addition, plasma coagulation was inhibitedhigher at pH 5.5 than at pH 7.4. Accordingly, the restoration of awhen the growth medium was adjusted to pH 5.4.[63]perturbed barrier is significantly accelerated at low pH.[3] The

Fatty acids decisively contribute to the inhibition of S. aureusfunctional protein levels found for glucocerebrosidase in atopicgrowth in vitro and in vivo.[64] S. aureus is resistant at pH 6.8 but atdermatitis are similar to those in healthy skin;[49,50] moreover, thepH 5.5 is highly sensitive to oleic acid,[65] a fatty acid known to beactivity of acidic sphingomyelinase was enhanced.[51] However,present in increased amounts in atopic stratum corneumfrom these data it cannot be concluded that the enzymes are notlipids.[39,47]inhibited by an increased stratum corneum pH in atopic dermatitis

because in these studies the enzymatic activities were measured ex The 3-dimensional structure of staphylococcus enterotoxins isvivo at pH 5.6. also influenced by the pH of the medium; staphylococcal entero-

toxin C2 (SEC2) showed large deviations from its normal geome-In addition, the increased corneal pH in atopic dermatitis mighttry at pH 5 compared with pH 8, with probable effects on itsdisturb the lamellar lipid organization in the intercellular matrix ofcatalytic activity.[66] The adhesion of S. aureus to human (HaCaThuman stratum corneum. Several groups have already demonstra-cells) keratinocytes in vitro increased with increasing pH val-ted that the formation of lamellar structures in stratum corneumues.[67] It also showed a maximum at pH 7.4 for corneocytes oflipid mixtures depends on an acidic pH in vitro.[52-54] These studiesatopic donors.[68] Therefore, an occlusive treatment of healthyhave shown that only partially ionized free fatty acids are capablehuman skin for 5 days not only increased the pH from 4.38 to 7.05of forming lamellar liquid crystals. This occurs at pH valuesbut also increased colonization of the skin with coagulase-negativebetween 4.5 and 6. Correspondingly, disturbances of lipid organi-staphylococci by up to 105.[69]zation, with an increased presence of gel phase relative to the

crystalline phase, were detected recently for the first time ex vivo In addition to the direct stimulatory effect of an increased skinin patients with atopic dermatitis.[55] surface pH on bacterial growth in atopic dermatitis, other indirect

regulatory factors need to be considered. Nitrate secreted withA serine protease (stratum corneum chymotryptic enzyme),sweat is converted to nitrite by bacteria. Reactive nitrogen specieswhich has an pH optimum of 8.0, has recently been identifiedare formed from nitrite in an acidic milieu, which together withwithin the stratum corneum. This protease is thought to be re-acidified nitrite provide a non-specific antibacterial defense mech-quired for the desquamation process at the surface of the stratumanism. This is also effective against S. aureus.[70] The extent tocorneum.[56] It may also play a role in the pathogenesis of atopicwhich this effect is impaired in atopic dermatitis is still unclear.dermatitis because its expression is drastically increased in chronic

lesions in these patients, and transgenic mice with increased Furthermore, a decreased antibacterial activity of cationic sub-enzyme activity exhibit skin conditions very similar to atopic stances, such as certain basic proteins, due to the reduced aciditydermatitis.[57] Furthermore, recent evidence has shown that neu- has been postulated as the cause of increased S. aureus coloniza-tralization and, moreso, alkalization of intact murine skin stimu- tion.[71] According to Chikakane and Takahashi,[71] S. aureus prod-lates interleukin-1α and tumor necrosis factor-α activation and ucts cause an aggravation of dermatitis with exudation, which inrelease in vivo, linked to a coactivation of serine proteases and a turn increases the pH further, resulting in enhanced bacterialresulting perturbation of permeability barrier homeostasis, stratum growth – a vicious cycle. More recently, a number of cationic, low



molecular weight antimicrobial peptides, such as cathelicidins and play a role in atopic dermatitis is still unknown. Changes in skinβ-defensins, have been identified as important components of the pH become clinically significant primarily because of the creationinnate immunity of the skin, as they exert broad antibacterial of a favorable environment for the growth of S. aureus. In addi-activity against Gram-negative and Gram-positive bacteria, in- tion, these changes may also exert an influence on the activity ofcluding S. aureus. The expression of cathelicidin LL 37 has been the enzymatic process of lipid metabolism in the stratum corneum,demonstrated in sweat,[72] and human β-defensin 2 (HBD-2) is which might contribute to the dramatic skin barrier anomalypackaged in the lamellar bodies and released with their contents observed in atopic dermatitis.into the intercellular space.[73] In fact, a deficient expression of Although clinical evidence for the effects of acidic treatmentthese antimicrobial peptides has recently been reported in atopic modalities is scarce, several different therapeutic consequencesdermatitis, in contrast to psoriatic skin.[74] resulting from these interconnections have been suggested. Syn-

Dermicidin, another antimicrobial peptide recently discovered thetic detergents with an acid pH should always be preferred overas a component of human sweat, also shows antimicrobial activity soap because of their growth-regulating effect and favorable safetyagainst a variety of pathogenic microorganisms, including S. aure- profile in atopic skin diatheses.[79] A number of comparativeus. While its activity against Escherichia coli and Enterococcus experimental studies, from Japan in particular, have shown benefi-fecalis was found to be somewhat pH insensitive, incubation of S. cial effects of the topical application of acidic electrolytic wateraureus with a sweat fraction containing dermicidin I induced (pH 2.0–2.7) on the severity of dermatitis and S. aureus coloniza->90% cell death when buffered at pH 5.5, but only approximately tion of the skin, both in children[80] and adults.[81] An increase in60% when buffered at pH 6.5.[75] the linoleic acid content of the stratum corneum lipids by 30%,

with a significant improvement in skin barrier function and defi-Fibronectin and fibrinogen have been reported to play a majornite improvement in skin condition, was observed when patientsrole in the enhanced binding of S. aureus to the skin of patientswith atopic dermatitis were treated for 15 days with a creamwith atopic dermatitis.[76] In an in vitro bacterial binding assay,containing not only 10% urea but also 5% sodium lactate, at a pHpre-treatment of S. aureus strains expressing fibronectin- andof 5.[82] Topical skincare preparations adjusted to pH 5 have alsofibrinogen-binding proteins with fibronectin or fibrinogen signifi-proved very effective for the prophylactic protection of atopic skincantly inhibited bacterial binding to atopic dermatitis skin, infrom irritant noxae.[83]contrast to preincubation with saline solution (pH 7.4). However,

the effects of a pre-treatment with solutions at lower pH values These findings are also meaningful with respect to the corne-were not reported. otherapeutic approach of atopic dermatitis, based on the efficacy

of appropriate moisturizers in preventing the development ofSphingolipids, such as sphingosine, which are released undercracking and fissuring in xerotic skin that facilitates the penetra-the influence of acid ceramidase, also have a strong growth-tion of aeroallergens, thereby preventing further development ofinhibitory effect on several microorganisms, including S. aure-atopic dermatitis.[84] They also corroborate the concept that manyus.[77] Both the ceramide content in the stratum corneum[23,45,47]

immune functions of the skin are both secondary and downstreamand the activity of acidic – rather than alkaline – ceramidase,(i.e. outside-in) with regard to atopic dermatitis, as recently pro-which releases sphingosine from ceramides, are significantly de-posed by Elias et al.[2]creased in atopic dermatitis.[41,78] As shown recently, the sphingo-

sine content of affected and uninvolved skin in atopic dermatitis is Taken together, these findings not only shed new light on thesignificantly reduced. In turn, this deficiency correlates with an pathogenic involvement of disturbed stratum corneum acidifica-increase in S. aureus colonization.[78] tion in atopic dermatitis, but also point to a number of opportuni-

ties for further clinical and experimental investigation on theIt could even be speculated that S. aureus itself causes anpathophysiological pH dependencies and their therapeutic impact.aggravation of barrier function disturbance by secreting an

enzyme-hydrolyzing ceramide. The origin of the enzyme sphingo-myelin deacylase, which shows an increased activity in atopic Acknowledgmentdermatitis,[41] still remains to be determined as either endogenous

The authors have provided no information on sources of funding or onor bacterial.[46]

conflicts of interest directly relevant to the content of this review.

4. Conclusion

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