The impact of recent advances in lipidomics and redox lipidomics on dermatological research

The skin lipidome in development and homeostasis

From the last trimester of fetal development to birth the human skin is covered by a protective layer termed vernix caseosa (VC), a mixture of water, proteins, and lipids that also contributes to the initial formation of the stratum corneum. To comprehensively address which lipids, in addition to ceramides, could provide the barrier and hypothetical signaling functions of VC, Checa et al. analyzed VC from 156 children classified as pre-term, full-term, and post-term [29]. Sphingolipids on the one hand and oxylipins plus endocannabinoid, on the other hand, were analyzed in two separate ESI-UPLC-MS/MS protocols (triple quadrupole detectors). One key finding of the study was that the ceramides/sphingomyelin ratio (only Cer[NS], the non-hydroxylated fatty acid/sphingosine backbone class, were analyzed) in VC significantly increased with gestational age, which, as the authors point out, may be required for dry-adaptation postpartum. The authors could also detect the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in VC, which have known signaling bioactivity in keratinocytes, as AEA regulates keratinocyte differentiation, and both mediators affect lipogenesis in epidermal cells. Additionally, 2-AG appears to be a pro-resolving factor for wound healing. Together these newly discovered bioactive lipids present in VC are compatible with functions of VC beyond being a mere barrier surrogate at birth. And indeed, a recent study by Boiten and colleagues demonstrates that a formulation based on known components of VC (whether endocannabinoids are included is not specified) can promote barrier recovery after tape stripping in healthy volunteers and alters lipid synthesis patterns. Using LC/MS, the authors showed that disruption-induced synthesis of ceramides with a total chain length of carbons was attenuated by the VC formulation, and esterified omega-acyl-ceramides (Cer[EO]) were increased. SC lipid organization was thus favorably changed to facilitate accelerated barrier restoration.

Ultraviolet irradiation and chemical skin stress

As the skin is the body’s outermost organ, it is constantly exposed to high oxygen levels, ultraviolet (UV) radiation, and environmental stress, such as pollution. Several groups have thus studied the effect of these exogenous factors on the lipid composition of the skin, and how these modifications in turn may affect skin biology. External insult can cause enzymatic and nonenzymatic (free radical or singlet oxygen mediated) oxidative modification or nitration or chlorination of cutaneous lipids. Cholesterol, phospholipids, and squalene are targets for nonenzymatic lipid oxidation and can yield bioactive products. Stress-induced activation of the epidermal lipoxygenases (ALOXE3 and ALOX12B), dermal lipoxygenases, and cyclooxygenase produce a wide variety of fatty acid-derived mediators, most prominently eicosanoid species. Also, endocannabinoid levels (via PLC activation) and ceramides are UV responsive, and the reader is referred to excellent recent reviews on that topic. Here we will merely discuss the very recent data on stress-induced changes to the(ox-) lipidome of the skin.

Dalmau and colleagues investigated the effect of acute and chronic solar simulator exposure on cultured primary keratinocytes, with twice-weekly irradiation with 0.7 J/cm2 of UVA in combination with 25 mg/cm2 of UVB for up to four weeks for the chronic group. Lipids were analyzed in two separate orthogonal acceleration time-of-flight (or-TOF) LC/MS runs, one for sphingolipids and one for all other detectable lipids, respectively. In the response to acute irradiation (one single irradiation) they found a decrease in the sphingomyelin to glucosylceramide ratio, and a strong increase in phospholipids, especially (34:0) and (36:2) phosphatidylcholines, whereas phosphatidyl-inositols were decreased. Furthermore, triacylglyceride (48:5) was elevated after acute exposure. The chronic irradiation (in total 8 exposures over four weeks) resulted in the elevation of long-chain ceramides and a decrease of sphingomyelin, as a result of sphingomyelinase activation which the authors had determined. Most prominently, a strong increase in lysophosphatidylcholine species was observed after chronic exposure. Together, the authors argue that the lipid composition after chronic exposure may present an early KC differentiation lipid signature which contains protein kinase C (PKC) agonistic lipids.

Skin inflammation, skin sensitization, and therapeutic interventions

Gluco corticosteroids (GC), by far the most common class of drugs used in the treatment and management of various inflammatory skin diseases cause side effects, atrophy of the skin, and epidermal barrier defects. Ropke and colleagues performed lipidomics with two separate UHPLCToF-MS approach for FFA and glycero-/sphingolipids, respectively. The analysis was performed on epidermal lipid extracts from tape strips collected from healthy volunteers after a 28-day treatment period, with once-daily applications of clobetasol (high potency GC) or betamethasone (medium potency GC) ointments at the site of collection. Both corticoids reduced stratum corneum thickness and increased trans-epidermal water loss, each an indicator of reduced barrier function. This was associated with a significant reduction of the epidermal specific, omega hydroxyl chain esterified ceramides. Furthermore, a significant decrease of ceramides with total chain lengths of C40 to C43 was observed among all other ceramide classes except Cer[NS] and Cer[AS], which remained unchanged. The analysis showed a decrease in triacylglycerols and saturated free fatty acids, but these two findings were dominant only in clobetasol (the super potent GC-) treated areas. The authors conclude that supplementation with long-chain ceramides may counteract treatment-induced atrophy and restore impaired barrier function.

Skin sensitization and allergic contact dermatitis are promising fields for the development of reliable predictive biomarkers. Santina and colleagues REF have analyzed phospholipid profiles of keratinocytes after exposure to the sensitizing chemical dinitrofluorobenzene (DNFB), the toll-like receptor (TLR) agonist lipopolysaccharide (LPS), and the irritant benzalkonium chloride (BC) in cell culture.

Author: Florian Grubera, Christopher Kremslehnera, Marie-Sophie Narzta