Abridged from the Dermatology Progress in Foundation Dermatology Editor: Alan N. Moshell , MD. Stratum Corneum Moisturization at the Molecular Level Anthony V. Rawlings, Ian R. Scott, Clive R. Harding, * and Paul A. Bowsed Unilever Research, Edgewater Laboratory, Edgewater, N ew Jersey, U .S.A.; ' Unilevcr Research, Colworth Laboratory, Sharnbrook, Bedford; and tUnilever Research, Port Sunlight Laboratory, Bebington, Wirral, U.K. n any living system, control of water translocation is essential corneocytes embedded in a lipid matrix (see Fig 1). The main func­ for survival. Being in close proximity to a non-aqueous envi­ tion of the epidermis is to produce the stratum corneum; a selec­ ronment this control is a fundamental property of our skin tively permeable outer layer that protects against water loss and and it uses mechanisms that are complex, elegant, and unique chemical insult. However, as will become evident from this review, in nature to achieve it. the barrier function of the stratum corneum is not its only function. IThe skin preserves water through intercellular occlusion (water The combination of the barrier properties of the stratum corneum permeability barrier) and cellular humectancy (natural moisturizing and its inherent cellular humectant capabilities moisturize the stra­ factor or NMF). The mechanisms for producing the water perme­ tum corneum, which is important for maintaining the flexibility of ability barrier and NMF are not only complex but also susceptible to the stratum corneum and its desquamation. The most characterized disturbance and perturbation. components of the stratum corneum are keratins, specialized cor­ This review begins with an overview of the vast amount of work neocyte envelope proteins, lipids, NMF, specialized adhesion struc­ that has led to a greater understanding of the mechanisms of mois­ tures (desmosomes), and enzymes. We will focus our attention on turization of the stratum corneum, including the nature of the water the last four components and discuss their relationship to stratum permeability barrier, and specifically examines the role of essential corneum moisturization. fatty acids, together with the role of NMF. The final parts of the review then examine the more recent knowledge on the biologic Barrier Lipids and the Role of Essential Fatty Acids General variation in barrier lipids (Variatiolls ill Stratum Comeum Lipids) and health is, in part, dependent on the nutritional balance of the diet other constituents that affect stratum corneum structure and func­ involving proteins, carbohydrates, lipids (saturated and unsatu­ tion, their variability, and particularly how they contribute to con­ rated), vitamins, and minerals. The inter-relationship between gen­ trolling moisturization and desquamation (New Irlsights illto Desqua­ eral health and skin health is reflected by the incidence of skin matioll and AbrlOrmal Desquamation: Comparisoll oj Ichthyoses and problems with nutritional deficiencies, e.g., scurvy, kwashiorkor, Xerosis) and finishes with a summary. and pellagra. For many decades it has been known that the absence of lipids in OVERVIEW the diet leads to unhealthy skin. In 1929 and 1930 Burr and Burr Stratum Corneum Structure Original histologic observations [1 ,2] showed that linoleic acid was an essential dietary requirement of the typical "basket weave" appearance of the stratum corneum in animals. Much later observations [3 - 6] indicated that the absence did not do justice to a full appreciation of its many functions that we of this essential fatty acid (EFA) from the diet results in a general know of today. Over the past three to four decades the stratum deterioration of the health of the animal and, specifically, in the corneum has been investigated by physical chemists, dermatolo­ development of a scaly skin condition with concomitant increase in gists, biologists, and more recently enzymologists. Initially consid­ trans-epidermal water loss. ered to be a homogeneous film, the stratum corneum has now been However, it was not until the late 1970s that Prottey and Houts­ shown to be a heterogenous structure composed of protein-enriched muller showed that the water permeability ofEFA-deficient skin of people [7] or animals [8] could be kept within normal ranges by Reprint requests to: Dr. Anthony V. Rawlings, Unilever Research, 45 direct topical application of linoleic acid or other EFA. Although River Road, Edgewater, NJ 07481. topically applied linoleic acid rapidly reversed the cutaneous mani­ Abbreviation: NMF, natural moisturizing factor; RXLI, recessive X­ festations of EFA deficiencies [5 - 8], the way it achieved this was linked ichthyosis. unknown. Potentially, the mechanism was postulated as the EFA Copyright © 1994 by Dermatology Foundation, 1560 Sherman Avenue, Evanston, Illinois 60201 731 732 RAWLINGS ET AL THE JOURNAL OF IN VESTIGATIVE DERMATOLOGY o I Desqt"lo UlnUn STUATUY OISJUNCTUU o Cornco...:yle STJUTU~! Ce latnide 1 L'Pld BUB. I ;_ -- -..J C OR~EU~! 115%) -"'"- ., -~~ $TIUTU.\J COYP"CTUY n l~·· bol.l d l.l.pJd- ? _ - 1 ~ O < H/O HI t ILl,j ,,0 eornco(.'ylc~ lhllubr uu: CO Atine ~..... <: I' UU\l l all ~ ~ O H 0 1-1 I OH OH I-,x "\... ,1:):1 L I lnmcllar ST J('\TU~ ! Ceral11ide 2 Ceramide 3 0 ·1 1 t1U .. kentob, .. Un ~ pi 1. ,. Innllill. GI!A:--1ULO Sm ! (22%) (16%) 01~ 0 01~ 0 NH ST!UTU~! NH 0 11 S P!:--10SU~1 0 1-1 0 11 ~OH m---- ~Cerarnid e 4/5 (23%) STRATm! . ' JJJJJJ UASALE O l-:" O 0 1 ' ~ 0 Figure 1. Schematic representation of the epidermis. NH OH NH 0 1-1 0 11 /,~ 0 OH ~0 11 ~O Ceramide 6 II acting as a simple structural component, or via conversion to prosta­ ("10% ) (14%) glandins. Although linoleic acid does have classical structural roles in, for Figure 3. Chemical structures of stratum corneum ceramides. example, phospholipids, the slight differences between, say, oleic and linoleic acid does not explain the huge differences in EFA defi­ ciencies when oleic acid replaces linoleic acid in phospholipids. The the epidermal water permeability barrier it had to meet two criteria. role ofEFAs in barrier function is also not via prostaglandin synthe­ It had to contain linoleic acid or a derivative and it had to be detect­ sis, as the essential first step of conversion from linoleic acid to ab le in the region where the major barrier existed: the stratum arachidonic acid does not occur in skin [8]. T he curing effect of corneum or more specificall y the stratum compactum [13]. Elucida­ li noleic.acid is also no~ inhibited by indomethacin, a powerful pros­ tion of the way in which linoleic acid and other essential fatty acids tagland1l1-synthetase 1I1hlbltor, and a similar benefit in reducing control the loss of water from the skin has only emerged during the scaliness/water loss can be obtained using columbinic acid, which structurally carmot be converted to prostaglandins [9]. The specific last 10 years. .The detailed and pioneering work of Gray and colleagues in the role of EFAs was thus not via either of the mechanisms posulated at ITI1d to l at~ 197?s was pivotal and catalytic in opening up the whole the time. field of sk1l1 lipid research. Up to this point, most of the skin lipid Although early researchers recognized that the epidermis was resear~h had centered on phosph~lipids , which although rich in more impermeable than the dermis, it was not until the early 1940s that the precise location of the barrier was thought to reside in the l1l10ieJc aCid could not be 111volved 111 the water permeability barrier as they are almost totally absent from the stratum corneum. While stratum corneum [10]. Twenty years later, using organic solvent extraction of the stratum corneum, Matoltsy et at [11] demonstrated Gray al~d co-workers we.re ide~tifying a number of glycolipids that lipids played a critical role in barrier function. Middleton fur­ p.rese~1t I? skl1~ (14), and d ! sc~venng a unique epidermal glycolipid ther demonstrated [12] that lipids were also important in preventing nch 111 lin?letc aC id [15], US111g electron microscopic techniques, the loss of NMF from inside the corneocytes. Thus, for a lipid Elias and IllS co-workers [16 -18] were visualizing the bilayer nature of lipids in between the stratum corneum cell s. component to have a key role in the formation or maintenance of Building on Gray's biochemical studies, two main research centers ~hen e1uc.idate~ the structures of the linoleate rich lipids o present 111 the eptdermls. Bowser and co-workers determined un­ e~uivoca lly the structure [~9 ,20] of the unique epidermal glycoli­ pid, the acylglucosylceralTI1de, but proved that in itself it could not Nil ? II,.OH 0 ~- 0 1 ' 1 be a barrier lipid as it was absent from the stratum compactum [13]. I \ Stmultaneously With Downing and Wertz's group [21- 26] at Iowa, 0 1-1 011 Bo:vser e/ al [27] discovered a new class of structurally related cer­ ~0 11 Acylglucosylceratnide (AGC) amJdes, one of which was rich in linoleic acid and present in the o stratum compactum (Ceramide 1 or acylceramide; Fig 2). Compar­ ~oI\N'-J\A/VWWVVVv/ Ison of the structures of glucosylceramides suggested that they were "'YOH precursors of related cerarnides with acy lglucosylceramide being \f\/VVVV\I;-AOI-I the precursor of Ceramide 1. Much later, in metabolic studies, this Acylceratnide (AC or Ceratnide '1) was shown to be true [28]. o .Following on from this work, several other types of glucosylcera­ o ~Ides and ceram ld ~s were also discovered. In addition to the major II li~oleoyl-nch speCles, five other chromatographically distinct cera­ Acylacid (AA) ITI1de and glucosylceramide classes could be separated and isolated Nil by thin-layer chromatography [23,29 - 31]. For the stratum cor­ ,(,0 11 neu~ ceramides these were named according to their polarity be­ \f\/VVVV\I;-AOI1 ~111nmg w~th the na~1e Ceramide 1 for the most non-polar and Sphingosine l1110lelc aCld - conta1l1111g species (Fig 3).