Autologous Th2-polarized lymphocytes induce atopic dermatitis lesions in non-atopic human skin xenotransplants.

BACKGROUND: The key signals that suffice to induce atopic dermatitis (AD) in human skin remain incompletely understood. Also, current mouse models reflect human AD only unsatisfactorily. Therefore, we have asked whether a humanized AD mouse model can be developed that reflects human AD more faithfully and permit to identify key signals that suffice to induce AD lesions in previously healthy human skin in vivo. METHODS: Healthy human skin from non-atopic donors was transplanted onto SCID/beige mice. After xenotransplant reinnervation by mouse sensory nerve fibers had occurred, mixed autologous human Th2 CD4+ and Tc2 CD8+ T cells that had been pretreated in vitro with IL-2, IL-4, and LPS were injected intradermally into the xenotransplants without skin barrier disruption. RESULTS: Injected non-atopic xenotransplants rapidly developed a morphological, functional, and immunological phenocopy of human AD lesions regarding skin barrier defects, immunopathology including intraepidermal eosinophils, mast cell activation, increase of thymic stromal lymphopoietin, eotaxin-1 and type 2 cytokine circuits, and even showed characteristic neuroimmunological abnormalities such as ß2-adrenergic receptor downregulation. The experimentally induced AD lesions in human skin responded to standard AD therapy (topical dexamethasone or tacrolimus; systemic anti-IL-4Rα antibody [dupilumab]), and relapsed when neurogenic skin inflammation was induced by exposing mice to perceived stress. CONCLUSIONS: This new animal model uniquely mimics the complexity of human AD and its clinical response to standard therapy and psychoemotional stressors in vivo, and shows that Th2-polarized lymphocytes associated with excessive IL-4Rα-mediated signaling suffice to induce human AD skin lesions, while atopy and epidermal barrier disruption are dispensable.

Malassezia restricta-mediated Lipoperoxidation: A Novel Trigger in Dandruff.

Dandruff is a common scalp disorder with multiple microbial and host-related factors contributing to its aetiology, including alterations in scalp sebum. Despite existing evidence that the yeast Malassezia restricta plays a key role in the onset of dandruff, the interplay of these factors is poorly understood. Recently, squalene monohydroperoxide and malondialdehyde were established as biomarkers of dandruff-afflicted scalp, highlighting the role of sebum lipoperoxidation in the triggering and maintenance of dandruff, although its mechanism of action is unknown. The current study provides evidence that M. restricta mediates sebum peroxidation, leading to production of squalene monohydroperoxide and malondialdehyde. Furthermore, in vitro data show that these lipoperoxidation products act on epidermal cells and alter the skin barrier. These results support the role of Malassezia restricta-induced lipoperoxides as triggers of dandruff, which suggests that blocking their production could be a novel anti-dandruff treatment approach.

A novel clinical method to measure skin staining reveals activation of skin damage pathways by cigarette smoke.

BACKGROUND: Long-term use of cigarettes can result in localised staining and aging of smokers' skin. The use of tobacco heating products (THPs) and electronic cigarettes (ECs) has grown on a global scale; however, the long-term effect of these products' aerosols on consumers' skin is unknown. This pilot clinical study aimed to determine whether THP or EC aerosol exposure results in skin staining or activation of biomarkers associated with oxidative stress. MATERIALS AND METHODS: Eight areas were identified on the backs of 10 subjects. Two areas were used for air control, and two areas exposed to 32-puffs of cigarette smoke (CS), THP or EC aerosols, which were delivered to the skin using a 3-cm diameter exposure chamber and smoke engine. Skin colour was measured using a Chromameter. Squalene (SQ), SQ monohydroperoxide (SQOOH) and malondialdehyde (MDA) levels were measured in sebum samples by mass spectrometry and catalase colorimetry. RESULTS: CS exposure significantly increased skin staining, SQOOH and MDA levels and SQOOH/SQ ratio. THP and EC values were significantly lower than CS; EC values being comparable to air control. THP values were comparable to EC and air control at all endpoints, apart from skin staining. SQ and catalase levels did not change with exposure. CONCLUSIONS: CS stained skin and activated pathways known to be associated with skin damage. THPs and ECs produced significantly lower values, suggesting they could offer hygiene and cosmetic benefits for consumers who switch exclusively from smoking cigarettes. Further studies are required to assess longer-term effects of ECs and THPs on skin function.

Anti-pollution effects of two antioxidants and a chelator-Ex vivo electron spin resonance and in vivo cigarette smoke model assessments in human skin.

BACKGROUND: Skin damage arising from pollutants in gaseous and particulate matter forms is mainly mediated by oxidative stress. The pollutants directly or indirectly generate free radicals on and in the skin, leading, for example, to MMP up-regulation and damage of collagen fibers. Antioxidants and chelators are used in anti-pollution cosmetics to reduce the harmful effects of free radical generation. MATERIALS AND METHODS: We investigated the efficacy of two antioxidants and one chelator in an anti-pollution cigarette smoke model. Free radical generation was measured directly after UV and cigarette smoke exposure ex vivo on pig skin (slaughterhouse waste), by use of Electron Spin Resonance (ESR). Effects of cigarette smoke were compared to those of Urban Dust (NIST-standard). ESR was also used to measure the copper chelation activity of the test products. Following cigarette smoke application in vivo, two markers of lipid peroxidation malondialdehyde (MDA), and squalene monohydroperoxide (SQOOH), were measured from swab solutions taken from the smoke-exposed skin sites. RESULTS: EDTA generated no effect and the non-chelator antioxidant Tocopherol only small antioxidant effects after exposed to cigarette smoke ex vivo as well as in vivo. Only the hydrophilic phenylethanoid H1 showed significant effects. A clear reduction of free radicals ex vivo and further a significant reduction of in vivo lipid peroxide formation was measured. CONCLUSION: The cigarette smoke model is an ideal method for in vivo assessment of anti-pollution efficacy of topical products with close relation to the real situation of subjects exposed to urban pollution. Further research is required to better understand the role of chelators in anti-pollution cosmetics.

Metrology and sensors as dermo-cosmetic technology opportunities for a change of paradigm.

OBJECTIVE: Metrology and measures are changing the way patients and consumers behave and help find new, more effective solutions. METHODS: This Review and Prospective Paper identifies applications in the field of dermatology and beauty tech. RESULTS: The review of skincare as well as dermatological applications and analysis provides a comprehensive picture of the dynamics in the process of impacting the complete value chain in the field of dermo-cosmetics, as well as the opportunities offered by a strict approach around new and innovative measures, especially in the field of better patient/consumer knowledge, understanding, and personalized solution offering. It identifies the new business models or opportunities for the cosmetic industry. CONCLUSION: Adapting metrology and measures to skincare is a significant opportunity to change the way things are done today.

Barrier disruption, dehydration and inflammation: Investigation of the vicious circle underlying dry skin.

OBJECTIVE: Many endogenous or exogenous factors, isolated or combined, can trigger dry skin disorder, leading to a water/lipids-depleted stratum corneum concomitant with uncomfortable rough and scaly skin surface. In a defensive reaction, the alteration of the skin barrier stimulates the production of cytokines to initiate homeostasis restoration but this can also induce an inflammatory response that further weakens the barrier. The two phenomena intertwining one another lead to the creation of a vicious circle, here called Inflamm'dryness, that maintains dry skin state. It is thus very important to investigate biological mechanisms involved in Inflamm'dryness to better manage dry skin. METHODS: A 3D model mimicking dry skin has been developed. Adjustment of tape stripping level allowed to reproduce skin barrier alterations and resulting inflammation involved in dry skin. The effect of Helichrysum stoechas extract on this downward spiral was then investigated to validate the concept. RESULTS: Tape-stripping permitted to successively remove the cell layers of the stratum corneum: the barrier function was altered and skin was inflamed creating a vicious circle, mimicking very dry skin prone to Inflamm'dryness. Helichrysum stoechas extract was not only able to resolve inflammation but also to reverse concurrently adverse tape-stripping effects and imparted significant structural and functional recovery of the barrier (e.g. on NMF and ceramides levels, TEWL, tissue organization). CONCLUSION: This 3D model reproduces Inflamm'dryness vicious circle present in dry skin and highlights the importance of breaking this process to improve dry skin conditions. Helichrysum stoechas extract is a promising active ingredient for the management of dry skin.

OBJECTIF: De nombreux facteurs endogènes ou exogènes, isoles ou combines, peuvent être à l'origine de sècheresse cutanée, conduisant à une peau en manque d'eau et de lipides : la peau tiraille, présente parfois un l'aspect rugueux (voire la présence de squames) et des sensations d'inconfort. Cette altération de la barrière cutanée induit la production de cytokines permettant la restauration de l'homéostasie de la peau mais induisant également une réponse inflammatoire fragilisant davantage la barrière cutanée. Ces deux phénomènes conduisent à la création d'un cercle vicieux, l'Inflamm'dryness, qui entretient l'état de sécheresse de la peau. Il semble donc important d'étudier les mécanismes biologiques impliqués dans le phénomène d'Inflamm'dryness afin de mieux prendre soin des peaux sèches. MÉTHODES: Un modèle 3D mimant une peau sèche a été développé. Un ajustement du nombre de tape-strippings a été nécessaire afin de reproduire les défauts de barrière ainsi que de l'inflammation caractéristiques des peaux sèches. L'effet d'un extrait d'Helichrysum stoechas sur cette spirale négative a ensuite été étudié pour valider le concept. RÉSULTATS: L'étape de tape-stripping a permis de retirer successivement les couches superficielles du stratum corneum: la fonction barrière est altérée et la peau est enflammée créant un cercle vicieux, mimant une peau très sèche sujette à l'Inflamm'dryness. L'extrait d'Helichrysum stoechas est non seulement capable de résoudre l'inflammation, mais également de restaurer la fonction barrière de la peau (quantités de NMF et de céramides, la perte insensible en eau, organisation des tissus…). CONCLUSION: Ce modèle 3D reproduit le cercle vicieux de l'Inflamm'dryness caractéristique des peaux sèches et met en évidence l'importance de rompre ce processus afin de remédier à la sécheresse cutanée. L'extrait d'Helichrysum stoechas développé est un actif prometteur pour le soin des peaux sèches.

A novel method for evaluating the effect of pollution on the human skin under controlled conditions.

BACKGROUND: Generally considered as a major risk factor for various respiratory diseases, air pollution can also have a significant impact on the skin. To date, there is a plethora of cosmetics products with "anti-pollution" claims. However, these claims have not been fully substantiated with robust scientific evidence and currently there is no standardized method in place for validating the anti-pollution efficacy of cosmetics products. MATERIALS AND METHODS: This article discusses an innovative Controlled Pollution Exposure System (CPES) which allows quantified administration of pollutants on the skin and analysis of their direct impact. Using CPES, human subjects were exposed to ambient dust and ozone and sebum were sampled and analyzed for biomarkers. RESULTS: Following exposure of human subjects' skin to either ambient dust(100-450 µg/cm3 ) or ozone(100-1000 ppb), analysis of sebum revealed a significant decrease in squalene concentration, and significant increases in squalene monohydroperoxide and malondialdehyde concentration. CONCLUSION: The findings demonstrate cutaneous oxidative stress induced by ambient dust and ozone. The findings also demonstrate the efficacy of CPES to accurately measure the direct effect of controlled gaseous and particulate pollutants on human skin and indicate that squalene, squalene monohydroperoxide and malondialdehyde may serve as potent biomarkers for evaluating potential anti-pollution claims of cosmetics products.

Comparing skin characteristics and molecular markers of xerotic foot skin between diabetic and non-diabetic subjects: An exploratory study.

BACKGROUND: Xerosis cutis of the feet is one of the most common skin conditions among type 2 diabetics. Whether skin dryness among diabetic patients is different from 'general' skin dryness is unclear. The overall aim was to compare the structure, function and molecular markers of dry and cracked foot skin between diabetics and non-diabetics. METHODS: The foot skin of 40 diabetics and 20 non-diabetics was evaluated. A clinical assessment of skin dryness was performed and transepidermal water loss, stratum corneum hydration, skin surface pH, epidermal thickness, skin roughness, elasticity and structural stiffness were measured. Ceramides, natural moisturizing factors, histamines, proteins and molecular markers of oxidative stress were analyzed based on a non-invasive sampling method for collection of surface biomarkers. RESULTS: The mean number of superficial fissures in the diabetic group was nearly three times higher than in the non-diabetic group (11.0 (SD 6.2) vs. 3.9 (SD 4.2)). The skin stiffness was higher in the diabetic group and the values of almost all molecular markers showed considerably higher values compared to non-diabetics. Malondialdehyde and glutathione were lower in the diabetic sample. CONCLUSIONS: The high number of superficial fissures may be based on an increased stiffness of dry diabetic foot skin combined with different concentrations of molecular markers in the stratum corneum compared to dry foot skin of non-diabetics.

Clinical Efficacy of a Novel Two-Part Skincare System on Pollution-Induced Skin Damage.

INTRODUCTION: Air pollution continues to be a global health concern and recent studies have shown that air pollutants can cause skin damage and skin aging through several pathways that induce oxidative stress, inflammation, apoptosis, and skin barrier dysfunction. Preventive measures need to be considered to retain optimal skin health, and topical skincare products may be able to alleviate the negative effects of air pollution on skin. A randomized, double-blind, placebo-controlled clinical usage study was conducted to assess the efficacy and tolerability of a novel two-part skincare system (LVS) that was developed to provide protection against environmental skin aggressors including air pollution. After 8 weeks of use in subjects exposed to extremely high levels of pollution, LVS provided significant improvements compared to placebo in all clinical efficacy parameters including crow's feet wrinkles, overall skin damage, skin tone evenness, tactile roughness, and visible redness. Subject self-assessment questionnaires showed that the treatment product was highly rated in self-perceived efficacy. Decreased SQOOH and MDA content in skin swab samples suggest that LVS helped to reduce oxidative stress in patients' skin. Histological analyses of biopsy samples using biomarkers related to skin structure, damage and function (collagen IV, MMP1, CPD, and CD1a) further support the clinical benefits of LVS. Altogether, the presented study is among the first to show that topical skincare products can help to reduce pollution-induced skin damage and improve skin quality, especially when specifically formulated with active ingredients that combat the harmful effects of air pollutants. J Drugs Dermatol. 2018;17(9):975-981.

Positive and ecobiological contribution in skin photoprotection of ectoine and mannitol combined in vivo with UV filters.

BACKGROUND: Chronic exposure to ultraviolet (UV) irradiation causes immunosuppression, photoaging, and carcinogenesis by induction of a cascade of skin damages. Sunscreens currently on the market are not absorbing UV rays uniformly throughout the full UV range, high sun protection factor (SPF) sunscreens absorb most of UVB rays but are less effective in absorbing the UVA part of the spectrum. In the context, one approach could consist of preserving the skin natural resources and mechanisms, which is the foundation of the ecobiological approach, by combing UV filters and antioxidants to enhance their photoprotective effect. METHODS: First, the photoprotection properties of ectoine and mannitol association were characterized by the quantification of glutathione, reactive oxygen species, and double-stranded DNA breaks and by the epidermal Langerhans cells functionality. Second, the protection of squalene oxidation, catalase activity, and trans-urocanic acid (UCA) by the ectoine and mannitol association combined or not with SPF30 UV filters was assessed in vivo via non-invasive skin samplings in 10 subjects on irradiated areas. RESULTS: Using in vitro irradiated skin cell models, we demonstrated that this association significantly preserved intracellular glutathione levels, reduced DNA strand breaks induced by oxidative stress, and maintained Langerhans cell functionality. In vivo this association combined with UV filters presented significantly higher protection of three natural defense systems altered by UV compared to UV filters alone: squalene oxidation, catalase activity, and preservation of trans-UCA. CONCLUSION: This study demonstrates the ecobiological potential of combining UV filters with biological protection to increase skin photoprotection provided by specific active ingredients with antioxidative and immunosuppressive properties.

Neryl acetate, the major component of Corsican Helichrysum italicum essential oil, mediates its biological activities on skin barrier.

Corsican Helichrysum italicum essential oil (HIEO) is characterized by high concentrations of neryl acetate, and we previously demonstrated that Corsican HIEO increases the expression of genes that are part of the differentiation complex (involucrin, small proline rich proteins, late cornified envelope, S100 protein family). The biological activities of HIEO and neryl acetate (NA) were compared to identify how NA contributes to HIEO activity on human skin. NA, as a part component of HIEO, was tested on skin explant models for 24 hours and 5 days in comparison with HIEO. We analyzed the biological regulations in the skin explant by transcriptomic analysis, skin barrier protein immunofluorescence, lipid staining and ceramide analysis by liquid chromatography-mass spectrometry. Transcriptomic analysis revealed that 41.5% of HIEO-modulated genes were also regulated by NA and a selected panel of genes were confirmed by qquantitative reverse transcription PCR analysis. Those genes are involved in epidermal differentiation, skin barrier formation and ceramide synthesis. Involucrin (IVL), involved in formation of the cornified envelope (CE), was upregulated at both gene and protein levels after 24 hours and 5 days respectively. After 5 days of treatment, total lipids and ceramides were also increased. Our results demonstrate that NA mediates a large part of Corsican HIEO activity on skin barrier formation.

A Dermocosmetic Significantly Reduces the Frequency and Intensity of Facial Skin Intolerability and Sensitivity in Subjects with Skin Intolerant to Skin Care Products and Sensitive Skin.

Introduction: Intolerance to dermocosmetics is frequent in subjects with allergic contact dermatitis (ACD). A dermocosmetic (DC) was developed to restore the natural skin barrier, to reduce skin inflammation and to improve sensitive skin in ACD. Objective: To assess the benefit of a DC in subjects with an allergic background and intolerance to cosmetic care, or with sensitive skin. Materials and Methods: In this open-label study, 107 subjects above 16 years of age applied DC on the face twice a day for 28 days. Assessments at Days 0, 14 and 28, included skin sensitivity, stinging test, local tolerance, transepidermal water loss (TEWL), skin hydration, inflammatory biomarkers (IL-1α, IL-1RA, PGE2) using tape stripping and subject satisfaction. Results: 88% were women and mean age was 42.0±15.0 years. Skin sensitivity at inclusion scored 5.9±0.35; 46% had ACD, 95% skin irritation, 92% sensitive skin and 88% intolerance to cosmetics. A significant (p<0.0001) 85% decrease of frequency and intensity of the composite score was observed at both endpoints. Stinging scores significantly (p<0.0001) decreased from 3.9 at baseline to 2.4 at Day 14 and 1.4 at Day 28; 77% and 81% of subjects reported improved skin reactivity at Day 14 and Day 28, respectively. Similar improvements were noted in the frequency and intensity of irritation, erythema, stinging, burning and discomfort. TEWL, skin hydration and inflammatory biomarker levels significantly (p<0.0001) improved. Overall subject satisfaction (85%) and tolerance (investigators: 99%, subjects: 97%) were high. Conclusion: DC significantly reduced the frequency and intensity of facial skin intolerability and sensitivity in subjects with skin intolerant to skin care products. Clinicaltrialsgov Identifier: NCT05487937.

The Actin-Based Motor Myosin Vb Is Crucial to Maintain Epidermal Barrier Integrity.

Myosin Vb (Myo5b) is an unconventional myosin involved in the actin-dependent transport and tethering of intracellular organelles. In the epidermis, granular keratinocytes accumulate cytoplasmic lamellar bodies (LBs), secretory vesicles released at the junction with the stratum corneum that participate actively in the maintenance of the epidermal barrier. We have previously demonstrated that LB biogenesis is controlled by the Rab11a guanosine triphosphate hydrolase, known for its ability to recruit the Myo5b motor. In order to better characterize the molecular pathway that controls LB trafficking, we analyzed the role of F-actin and Myo5b in the epidermis. We demonstrated that LB distribution in granular keratinocytes was dependent on a dynamic F-actin cytoskeleton. Myo5b was shown to be highly expressed in granular keratinocytes and associated with corneodesmosin-loaded LB. In reconstructed human epidermis, Myo5b silencing led to epidermal barrier defects associated with structural alterations of the stratum corneum and a reduced pool of LB showing signs of disordered maturation. Myo5b depletion also disturbed the expression and distribution of both LB cargoes and junctional components, such as claudin-1, which demonstrates its action on both LB trafficking and junctional complex composition. Together, our data reveal the essential role of Myo5b in maintaining the epidermal barrier integrity.

Rab11a Is Essential for Lamellar Body Biogenesis in the Human Epidermis.

Most of the skin barrier function is attributable to the outermost layer of the epidermis, the stratum corneum, which is composed of flattened, anucleated cells called corneocytes surrounded by a lipid-enriched lamellar matrix. The composition of the stratum corneum is directly dependent on the underlying granular keratinocytes, which are the last living cells in the stratified epidermis. Many components present in the intercorneocyte matrix are delivered by the underlying granular keratinocytes through a secretion process dependent on lysosome-related organelles called lamellar bodies. Because of the importance of lamellar bodies in the maintenance of the epidermal barrier, the mechanisms regulating their biogenesis must be better understood. In this study, we show that the Rab11a GTPase is highly expressed in terminally differentiated keratinocytes, where it is partly associated with lamellar bodies. Rab11a silencing in three-dimensional in vitro reconstructed human epidermis induces a barrier defect, a decrease in the amount of lipid found in the stratum corneum, a reduction in lamellar body density and secretion areas in granular keratinocytes, and the mis-sorting of lamellar body cargoes being driven to the lysosomal degradation pathway. Our results highlight the importance of Rab11a-dependent regulation of lamellar body biogenesis in keratinocytes and consequently on epidermal barrier homeostasis.

Exploration of scalp surface lipids reveals squalene peroxide as a potential actor in dandruff condition.

Dandruff is a common but complex disorder with three major contributing factors: (1) individual predisposition, (2) scalp sebum and (3) Malassezia yeast colonization. To obtain further insights into the role of sebum in dandruff biogenesis, we analyzed scalp lipid species in a cohort of ten dandruff-free (control) and ten dandruff-afflicted volunteers by gas chromatography coupled to mass spectrometry. Lipid peroxidation levels and biochemical markers of oxidative stress were also assessed. Squalene, a major sebum component, was significantly more peroxidized in dandruff-affected scalps, resulting in significantly higher ratios of squalene monohydroperoxide (SQOOH)/squalene. This was observed when comparing dandruff-affected zones of dandruff subjects to both their non-affected zones and control subjects. In addition, other biomarkers such as malondialdehyde indicated that oxidative stress levels were raised on dandruff scalps. Surprisingly, differences regarding either free or bound fatty acids were fairly rare and minor. Certain novel findings, especially squalene peroxidation levels, were then confirmed in a validation cohort of 24 dandruff-affected subjects, by comparing dandruff-affected and non-dandruff zones from the same individuals. As SQOOH can induce both keratinocyte inflammatory responses and hyperproliferation in vitro, we hypothesized that increased SQOOH could be considered as a new etiological dandruff factor via its ability to impair scalp barrier function. Our results also indicated that Malassezia could be a major source of squalene peroxidation on the scalp.