Skin Barrier Insights: From Bricks and Mortar to Molecules and Microbes

toms suggesting that other factors are also important in disease progression.¹⁸ Furthermore, filaggrin expression is downregulated in all AD patients, even those with no demonstrable filaggrin gene mutations,¹⁹ and this may be secondary to the enhanced Th2 cytokine milieu that suppresses the expression of differentiation-associated proteins.^20,21 Moisturizers can help restore enzyme activity by supplying humectants, to augment skin’s natural moisturizing systems, and occlusives, to retard water loss thus promoting desquamation and reduced scaling.Lamellar Lipids Lamellar lipids are stored as precursors in LG and secreted at the interface of the SG and SC.²² Enzymes that process these lipids to mature forms are also packaged in and secreted by LG.²³ Comprised primarily of ceramides, cholesterol, and fatty acids, (in an approximate molar ratio of 1:1:1) with small amounts of cholesterol sulfate and cholesterol esters, the extracellular lipids form a highly ordered structure that resists the flux of water. The effectiveness of this lipid matrix is highly dependent on the relative proportions of the major lipid classes²⁴ and is altered in xerosis,^25,26 aging,^26,27 and AD.^28,29 The structure of the individual lipid species also affects barrier quality. Ceramides and free fatty acids with longer acyl chains tend to form highly ordered, orthorhombic phases while shorter acyl chain variants form less ordered hexagonal phases.³⁰ The acyl chain length of SC ceramides in AD is shorter and correlates with decreased lipid order and barrier function.³¹ Lipid order as measured by FTIR is also significantly decreased in dry skin subjects.³² Perhaps as many as 1000 species of free ceramides and corneocyte-bound ceramides have been identified in SC33-35 (Figure 2). While most ceramide-derived fatty acids are saturated with acyl chain lengths of between 16 and 32 carbons, there exist some very long carbon chain lengths (30 to 34) that are particularly important in SC function³⁶; these are the ω-hydroxy ceramides that contain the unsaturated essential fatty acid (EFA), linoleic acid, esterified to the fatty acid. It is the ω-hydroxy ceramides that become covalently bound to the CE forming the CLE and act as scaffolding for the free ceramides that comprise the intercellular lipid bilayers. Two lipoxygenases process the ω-hydroxy ceramides prior to incorporation into the CLE.³⁷ Lipoxygenases are usually associated with arachidonic acid metabolism and inflammation. However, 12RLOX and 3eLOX3 sequentially oxidize the linoleic acid moiety and this processing is required for ester formation between ceramide and CE proteins (Figure 3). Ultimately degradation of ceramides may also be required for reduced cohesivity and desquamation and this is accomplished by the action of acid and alkaline ceramidases in the SC.³⁸ A novel model of SC lipid organization was proposed by Norlen and colleagues in which the ceramides are fully extended or “splayed’³⁹ (Figure 3) and this conformation was confirmed by infrared spectroscopy.⁴⁰ The proposed structure contrasts with the previously described sandwich model in which ceramides were represented in a folded position.⁴¹ The question of how fatty acids contained in moisturizers and cleansers interact with SC and affect lipid organization is pertinent. Bouwstra and colleagues demonstrated that topically applied C16 fatty acids are elongated to C24 and 26. Furthermore, these fatty acids integrated into the lamellar structure and increased lipid order.⁴² This suggests that topical application of the appropriate fatty acid can be used to improve the permeability barrier in compromised skin.Acid Mantle The pH of healthy SC is acidic and several potential acidifying mechanisms have been identified.⁴³ Acidification is important