Spatial transcriptomics reveals altered lipid metabolism and inflammation-related gene expression of sebaceous glands in psoriasis and atopic dermatitis.

Sebaceous glands drive acne, however, their role in other inflammatory skin diseases remains unclear. To shed light on their potential contribution to disease development, we investigated the spatial transcriptome of sebaceous glands in psoriasis and atopic dermatitis patients across lesional and non-lesional human skin samples. Both atopic dermatitis and psoriasis sebaceous glands expressed genes encoding key proteins for lipid metabolism and transport such as ALOX15B, APOC1, FABP7, FADS1/2, FASN, PPARG, and RARRES1. Also, inflammation-related SAA1 was identified as a common spatially variable gene. In atopic dermatitis, genes mainly related to lipid metabolism (e.g. ACAD8, FADS6, or EBP) as well as disease-specific genes, i.e., Th2 inflammation-related lipid-regulating HSD3B1 were differentially expressed. On the contrary, in psoriasis, more inflammation-related spatially variable genes (e.g. SERPINF1, FKBP5, IFIT1/3, DDX58) were identified. Other psoriasis-specific enriched pathways included lipid metabolism (e.g. ACOT4, S1PR3), keratinization (e.g. LCE5A, KRT5/7/16), neutrophil degranulation, and antimicrobial peptides (e.g. LTF, DEFB4A, S100A7-9). In conclusion, our results show that sebaceous glands contribute to skin homeostasis with a cell type-specific lipid metabolism, which is influenced by the inflammatory microenvironment. These findings further support that sebaceous glands are not bystanders in inflammatory skin diseases, but can actively and differentially modulate inflammation in a disease-specific manner.

Linoleic Acid Induced Changes in SZ95 Sebocytes-Comparison with Palmitic Acid and Arachidonic Acid.

Linoleic acid (LA) is an essential omega-6 polyunsaturated fatty acid (PUFA) derived from the diet. Sebocytes, whose primary role is to moisturise the skin, process free fatty acids (FFAs) to produce the lipid-rich sebum. Importantly, like other sebum components such as palmitic acid (PA), LA and its derivative arachidonic acid (AA) are known to modulate sebocyte functions. Given the different roles of PA, LA and AA in skin biology, the aim of this study was to assess the specificity of sebocytes for LA and to dissect the different roles of LA and AA in regulating sebocyte functions. Using RNA sequencing, we confirmed that gene expression changes in LA-treated sebocytes were largely distinct from those induced by PA. LA, but not AA, regulated the expression of genes related to cholesterol biosynthesis, androgen and nuclear receptor signalling, keratinisation, lipid homeostasis and differentiation. In contrast, a set of mostly down-regulated genes involved in lipid metabolism and immune functions overlapped in LA- and AA-treated sebocytes. Lipidomic analyses revealed that the changes in the lipid profile of LA-treated sebocytes were more pronounced than those of AA-treated sebocytes, suggesting that LA may serve not only as a precursor of AA but also as a potent regulator of sebaceous lipogenesis, which may not only influence the gene expression profile but also have further specific biological relevance. In conclusion, we have shown that sebocytes are able to respond selectively to different lipid stimuli and that LA-induced effects can be both AA-dependent and independent. Our findings allow for the consideration of LA application in the therapy of sebaceous gland-associated inflammatory skin diseases such as acne, where lipid modulation and selective targeting of AA metabolism are potential treatment options.

Antimicrobial Peptide Loss, Except for LL-37, is not Characteristic of Atopic Dermatitis.

Atopic dermatitis is an inflammatory skin disease characterized by significant permeability barrier damage. Regulation and maintenance of permeability and antimicrobial skin barriers are strongly connected. There is a lack of comprehensive studies of the expression of all 5 major antimicrobial peptide functional groups in atopic dermatitis. The aim of this study was to investigate the major antimicrobial peptide functional groups in lesional atopic dermatitis, non-lesional atopic dermatitis, and healthy control samples, using real-time quantitative PCR and immunohistochemistry. Lesional psoriatic skin was also examined as a diseased control. No differences in mRNA levels were detected between non-lesional atopic dermatitis and healthy control skin, and, at the protein level, the only change was the significantly decreased LL-37 in non-lesional atopic dermatitis. In lesional atopic dermatitis, several antimicrobial peptides were significantly altered at the mRNA level, while, at the protein level, all antimicrobial peptides were significantly upregulated or unchanged, except for LL-37, which decreased, compared with healthy controls. Antimicrobial peptides were similarly elevated in lesional atopic dermatitis and lesional psoriatic skin, with somewhat higher expression in lesional psoriatic skin, except for LL-37. In conclusion, LL-37 was the only antimicrobial peptide that was impaired in both non-lesional and lesional atopic dermatitis, highlighting its potential pathogenetic or exacerbating role in the initial stages of the disease.

Cytokine profile of the epidermis is region specific and may determine the characteristics of inflammation.

Recent data indicate that distinct skin areas show different microbial/chemical milieu. Keratinocytes (KC) respond to these stimuli by producing cytokine mediators. Therefore, we aimed to determine KC-derived cytokine expression in distinct healthy skin regions (gland-poor [GP], sebaceous gland-rich [SGR] and apocrine gland-rich [AGR]), and their changes in skin diseases of the given regions (atopic dermatitis [AD], papulopustular rosacea [PPR] and psoriasis). Cytokines were analysed at the mRNA and protein levels, and literature analysis was performed for functional categorization. The three regions showed characteristically different cytokine patterns. GP was featured by an IL-25/IL-33/IL-36RA/IL-38/IL-18 cytokine milieu, SGR was characterized by IL-23/IL-17C/IL-18, and AGR skin exhibited a mixed IL-25/IL-33/IL-23/IL-18 profile. Literature analyses revealed different homeostatic and proinflammatory roles of these cytokine patterns (Th2 related in GP, Th17 related in SGR and mixed Th2/Th17 in AGR). In skin diseases which are primarily epidermal cytokine-driven (AD, PPR), the level of the regionally characteristic cytokines were further elevated, in contrast to the autoantigen-driven psoriasis, where the cytokine pattern was independent from the localization. Healthy skin regions are equipped with different KC-derived cytokine profiles, which may influence each region's capability of mediator production in certain types of dermatoses.

Barrier function-related genes and proteins have an altered expression in acne-involved skin.

BACKGROUND: Acne vulgaris provides a unique disease setting in which a prominent skin inflammation is coupled with the overproduction of lipid-rich sebum. OBJECTIVES: Our goal was to evaluate the expression of barrier molecules in papular acne skin samples obtained from untreated patients and compare those to the results of healthy and of papulopustular rosacea-involved ones at the mRNA and protein levels. In addition, we aimed to assess the effects of various sebum composing lipids on the expression of proteins involved in barrier formation in keratinocytes. METHODS: Available microarray data sets of papular acne and papulopustular rosacea-affected skin samples were re-analysed with a focus on epidermal barrier-related pathways. Immunohistochemistry was performed to detect barrier molecules in the interfollicular regions of human acne and healthy skin samples. Protein levels of barrier-related genes were measured by western blot in samples of HaCaT keratinocytes treated with selected lipids. RESULTS: Meta-analysis of whole transcriptome data sets revealed that barrier-related pathways are significantly affected in acne vulgaris skin samples. While an altered expression of key molecules in maintaining barrier functions such as filaggrin, keratin 1, involucrin, desmoglein 1, kallikrein 5 and 7, was also observed at the protein levels, our data demonstrated that sebum composing lipids may selectively modify the levels of epidermal barrier-related molecules. CONCLUSIONS: Our results suggest that although not as prominently as in the dry papulopustular rosacea skin, the epidermal barrier in the interfollicular region may be damaged also in the lipid-rich skin samples of papular acne. Furthermore, our findings indicating diverse regulatory effects of various sebum lipids on the expression of barrier molecules in keratinocytes suggest, that they may influence the moisturization of the skin as well. Altogether, our findings could have implications in the development of sebum-modulating anti-acne therapies and even in the care of symptom-free skin.

New Data on the Features of Skin Barrier in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a Th1/17-driven inflammatory skin disease of the apocrine gland-rich (AGR) skin regions, where keratinocytes seem to be the crucial drivers of the initial pathogenic steps. However, the possible role of permeability barrier alteration in activating keratinocytes during HS development has not been clarified. We compared the major permeability barrier elements of non-lesional HS (HS-NL; n = 10) and lesional HS (HS-L; n = 10) skin with healthy AGR regions (n = 10) via RT-qPCR and immunohistochemistry. Stratum corneum components related to cornified envelope formation, corneocyte desquamation and (corneo)desmosome organization were analyzed along with tight junction molecules and barrier alarmins. The permeability barrier function was also investigated with transepidermal water loss (TEWL) measurements (n = 16). Junction structures were also visualized using confocal microscopy. At the gene level, none of the investigated molecules were significantly altered in HS-NL skin, while 11 molecules changed significantly in HS-L skin versus control. At the protein level, the investigated molecules were similarly expressed in HS-NL and AGR skin. In HS-L skin, only slight changes were detected; however, differences did not show a unidirectional alteration, as KRT1 and KLK5 were detected in decreased levels, and KLK7, KRT6 and DSG1 in increased levels. No significant differences in TEWL or the expression of junction structures were assessed. Our findings suggest that the permeability barrier is not significantly damaged in HS skin and permeability barrier alterations are not the driver factors of keratinocyte activation in this disease.

Psoriatic arthritis and its special features predispose not only for osteoporosis but also for fractures and falls.

Limited data are available on the predisposing factors to fractures and falls of patients with psoriatic arthritis (PsA). Our study intended to explore the differences between PsA patients and controls, concerning bone mineral density (BMD), the 10-year fracture risk, the number of prevalent fractures, the frequency of falls and to investigate the association of the same factors with PsA disease characteristics within the PsA group. Medical reports of 61 PsA patients and 69 consecutive, age-matched controls were analyzed, physical examination and bone mineral density (BMD, and T-score) were performed, and the 10-year fracture risk was calculated. The results were subjected to statistical analysis. Femoral neck BMD, as well as vertebral and femoral neck T-scores were lower, the odds ratio (OR) for low BMD and the 10-year risk of hip fracture was higher (p = 0.0029; 0.0002, p < 0.0001, OR = 21,9, p = 0.014) in the PsA group. The PsA patients were more predisposed to prevalent fractures, including peripheral fractures, and vertebral fractures as well as falls (OR 3.42; 2.26; 13.33; 3.95, respectively), compared to controls. Within the PsA group (beyond the age) scalp psoriasis and late-onset psoriasis, were significantly associated with a greater number of prevalent fractures (p = 0.0049; 0.029), while the number of falls per year correlated with late-onset psoriasis and the flexural psoriasis (p = 0.007; 0.023). Our results suggest that PsA is an independent risk factor for reduced bone density and falls hence to related bone fractures. Patients with late-onset psoriasis are more likely to suffer falls and related fractures, especially if their disease is characterized by the involvement of the hairy scalp and body folds.

Sebaceous immunobiology - skin homeostasis, pathophysiology, coordination of innate immunity and inflammatory response and disease associations.

This review presents several aspects of the innovative concept of sebaceous immunobiology, which summarizes the numerous activities of the sebaceous gland including its classical physiological and pathophysiological tasks, namely sebum production and the development of seborrhea and acne. Sebaceous lipids, which represent 90% of the skin surface lipids in adolescents and adults, are markedly involved in the skin barrier function and perifollicular and dermal innate immune processes, leading to inflammatory skin diseases. Innovative experimental techniques using stem cell and sebocyte models have clarified the roles of distinct stem cells in sebaceous gland physiology and sebocyte function control mechanisms. The sebaceous gland represents an integral part of the pilosebaceous unit and its status is connected to hair follicle morphogenesis. Interestingly, professional inflammatory cells contribute to sebocyte differentiation and homeostasis, whereas the regulation of sebaceous gland function by immune cells is antigen-independent. Inflammation is involved in the very earliest differentiation changes of the pilosebaceous unit in acne. Sebocytes behave as potent immune regulators, integrating into the innate immune responses of the skin. Expressing inflammatory mediators, sebocytes also contribute to the polarization of cutaneous T cells towards the Th17 phenotype. In addition, the immune response of the perifollicular infiltrate depends on factors produced by the sebaceous glands, mostly sebaceous lipids. Human sebocytes in vitro express functional pattern recognition receptors, which are likely to interact with bacteria in acne pathogenesis. Sex steroids, peroxisome proliferator-activated receptor ligands, neuropeptides, endocannabinoids and a selective apoptotic process contribute to a complex regulation of sebocyte-induced immunological reaction in numerous acquired and congenital skin diseases, including hair diseases and atopic dermatitis.

Plasma Levels of Bioactive Vitamin D and A5 Ligands Positively Correlate with Clinical Atopic Dermatitis Markers.

BACKGROUND: Over the past decade, several controversial studies described a relationship between vitamin D and atopic diseases. Low plasma vitamin D levels or even vitamin D deficiency was associated with an increased incidence of atopic disease, postulating that a higher dietary intake of vitamin D may be a beneficial strategy against atopic diseases such as atopic dermatitis (AD). OBJECTIVE: Our aim was to determine the relationship between plasma 25-hydroxyvitamin D3 (25(OH)D3) levels, the levels of the ligand of the vitamin D receptor (VDR) heterodimerization partner as well as the retinoid X receptor (RXR) and the active vitamin A5 derivative 9-cis-13,14-dihydroretinoic acid (9CDHRA) and AD severity. METHODS/RESULTS: Samples from AD patients (n = 20) and healthy volunteers (n = 20) were assessed. In our study, the frequently measured VDR ligand precursor 25(OH)D3 in addition to the VDR-ligand 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 9CDHRA displayed no different levels when compared with the plasma of AD patients and healthy volunteers. When performing further correlation studies focusing on AD patients, plasma 25(OH)D3 levels showed a negative correlation with eosinophils in blood (EOS) and SCORing Atopic Dermatitis (SCORAD) values, while 1,25(OH)2D3 and 9CDHRA levels correlated positively with plasma IgE, EOS, and SCORAD values. CONCLUSION: In consequence, the metabolic activation of vitamin D from 25(OH)D3 towards 1,25(OH)2D3 as well as the co-liganding of the RXR by 9CDHRA may be an important signalling mechanism, an important marker for AD development and severity as well as the basis for novel nutritional and pharmaceutical AD treatment options.

International eDelphi Study to Reach Consensus on the Methotrexate Dosing Regimen in Patients With Psoriasis.

Importance: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. Objective: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. Design, Setting, and Participants: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). Main Outcomes and Measures: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. Results: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients. Conclusions and Relevance: In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.

Research Techniques Made Simple: Lipidomic Analysis in Skin Research.

Although lipids are crucial molecules for cell structure, metabolism, and signaling in most organs, they have additional specific functions in the skin. Lipids are required for the maintenance and regulation of the epidermal barrier, physical properties of the skin, and defense against microbes. Analysis of the lipidome-the totality of lipids-is of similar complexity to those of proteomics or other omics, with lipid structures ranging from simple, linear, to highly complex structures. In addition, the ordering and chemical modifications of lipids have consequences on their biological function, especially in the skin. Recent advances in analytic capability (usually with mass spectrometry), bioinformatic processing, and integration with other dermatological big data have allowed researchers to increasingly understand the roles of specific lipid species in skin biology. In this paper, we review the techniques used to analyze skin lipidomics and epilipidomics.

miR-146a modulates TLR1/2 and 4 induced inflammation and links it with proliferation and lipid production via the indirect regulation of GNG7 in human SZ95 sebocytes.

Activation of Toll-like receptors (TLR) 1/2 and 4 are central in inducing inflammation in sebocytes by regulating the expression of protein coding mRNAs, however the microRNA (miRNA) profile in response to TLR activation and thus the possible role of miRNAs in modulating sebocyte functions has not been elucidated. In this work we identified miR-146a to have the highest induction in the TLR1/2 and 4 activated SZ95 sebocytes and found that its increased levels led to the down-regulation of IL-8 secretion, decreased the chemoattractant potential and stimulated the proliferation of sebocytes. Assessing the gene expression profile of SZ95 sebocytes treated with a miR-146a inhibitor, the induction of GNG7 was one of the highest, while when cells were treated with a miR-146a mimic, the expression of GNG7 was down-regulated. These findings correlated with our in situ hybridization results, that compared with control, miR-146a showed an increased, while GNG7 a decreased expression in sebaceous glands of acne samples. Further studies revealed, that when inhibiting the levels of GNG7 in SZ95 sebocytes, cells increased their lipid content and decreased their proliferation. Our findings suggest, that miR-146a could be a potential player in acne pathogenesis by regulating inflammation, inducing proliferation and, through the indirect down-regulation of GNG7, promoting the lipid production of sebocytes.

Leptin Receptor (rs1137101) and Brain-Derived Neurotrophic Factor (rs925946) Gene Variants Are Associated with Obesity in the Early- but Not in the Late-Onset Population of Hungarian Psoriatic Patients.

BACKGROUND: Psoriatic patients have considerably higher odds of being obese compared with the general population; however, the exact pathophysiological link between psoriasis and obesity needs to be elucidated. METHODS: To investigate the association of psoriasis with established obesity-related gene variants, we conducted a population-based case-control study including 3541 subjects (574 psoriasis cases and 2967 controls from the general Hungarian population). Genotyping of 20 SNPs at ADIPOQ, BDNF, FTO, GNPDA2, LEPR, MC4R, NEGR1, NPY, PPARG, TMEM18, and UCP2 were determined, and differences in genotype and allele distributions were investigated. Multiple logistic regression analyses were implemented. RESULTS: Analysis revealed an association between the G allele of the rs1137101 polymorphism (LEPR gene) and obesity risk (OR: 3.30 (1.45; 7.50), p = 0.004) in the early-onset group of psoriatic patients. Furthermore, the T allele of rs925946 polymorphism (BDNF gene) was also associated with increased risk of obesity in early-onset psoriasis (OR: 2.26 (1.24; 4.14), p = 0.008). CONCLUSIONS: Our results suggest that in psoriatic patients, there are prominent differences in the causes of obesity that should be accounted for, including not only environmental factors but also patient characteristics, such as the time of disease onset as well as genetic factors.

Alcohol in Psoriasis-From Bench to Bedside.

Alcohol affects the symptoms, compliance and comorbidities as well as the safety and efficacy of treatments in psoriatic patients. In this review, we aim to summarize and link clinical observations with a molecular background, such as signaling pathways at the cellular level and genetic variations, and to provide an overview of how this knowledge could influence our treatment selection and patient management.

Epidermal Growth Factor Modulates Palmitic Acid-Induced Inflammatory and Lipid Signaling Pathways in SZ95 Sebocytes.

Epidermal growth factor (EGF) acts as a paracrine and autocrine mediator of cell proliferation and differentiation in various types of epithelial cells, such as sebocytes, which produce the lipid-rich sebum to moisturize the skin. However, sebum lipids via direct contact and by penetrating through the epidermis may have regulatory roles on epidermal and dermal cells as well. As EGF receptor (EGFR) is expressed throughout the proliferating and the lipid-producing layers of sebaceous glands (SGs) in healthy and acne-involved skin, we investigated the effect of EGF on SZ95 sebocytes and how it may alter the changes induced by palmitic acid (PA), a major sebum component with bioactive roles. We found that EGF is not only a potent stimulator of sebocyte proliferation, but also induces the secretion of interleukin (IL)6 and down-regulates the expression of genes involved in steroid and retinoid metabolism. Importantly, when applied in combination with PA, the PA-induced lipid accumulation was decreased and the cells secreted increased IL6 levels. Functional clustering of the differentially regulated genes in SZ95 sebocytes treated with EGF, PA or co-treated with EGF+PA further confirmed that EGF may be a potent inducer of hyperproliferative/inflammatory pathways (IL1 signaling), an effect being more pronounced in the presence of PA. However, while a group of inflammatory genes was up-regulated significantly in EGF+PA co-treated sebocytes, PA treatment in the absence of EGF, regulated genes only related to cell homeostasis. Meta-analysis of the gene expression profiles of whole acne tissue samples and EGF- and EGF+PA -treated SZ95 sebocytes showed that the EGF+PA co-activation of sebocytes may also have implications in disease. Altogether, our results reveal that PA-induced lipid accumulation and inflammation can be modulated by EGF in sebocytes, which also highlights the need for system biological approaches to better understand sebaceous (immuno)biology.

Factor XIII-A in Diseases: Role Beyond Blood Coagulation.

Multidisciplinary research from the last few decades has revealed that Factor XIII subunit A (FXIII-A) is not only involved in blood coagulation, but may have roles in various diseases. Here, we aim to summarize data from studies involving patients with mutations in the F13A1 gene, performed in FXIII-A knock-out mice models, clinical and histological studies assessing correlations between diseases severity and FXIII-A levels, as well as from in vitro experiments. By providing a complex overview on its possible role in wound healing, chronic inflammatory bowel diseases, athe-rosclerosis, rheumatoid arthritis, chronic inflammatory lung diseases, chronic rhinosinusitis, solid tumors, hematological malignancies, and obesity, we also demonstrate how the field evolved from using FXIII-A as a marker to accept and understand its active role in inflammatory and malignant diseases.

Topical Vitamin D Receptor Antagonist/Partial-Agonist Treatment Induces Epidermal Hyperproliferation via RARγ Signaling Pathways.

Vitamin D and A derivatives are well-known endogenous substances responsible for skin homeostasis. In this study we topically treated shaved mouse skin with a vitamin D agonist (MC903) or vitamin D antagonist/partial agonist (ZK159222) and compared the changes with acetone (control treatment) treatment for 14 days. Topical treatment with ZK159222 resulted in increased expression of genes involved in retinoic acid synthesis, increased retinoic acid concentrations and increased expression of retinoid target genes. Clustering the altered genes revealed that heparin-binding epidermal growth factor-like growth factor, the main driver of epidermal hyperproliferation, was increased via RARγ-mediated pathways, while other clusters of genes were mainly decreased which were comparable to the changes seen upon activation of the RARα-mediated pathways. In summary, we conclude that epidermal hyperproliferation of mouse skin in response to a topically administered vitamin D receptor antagonist/partial agonist (ZK159222) is induced via increased retinoic acid synthesis, retinoic acid levels and increased RARγ-mediated pathways.

Adipokines in the Skin and in Dermatological Diseases.

Adipokines are the primary mediators of adipose tissue-induced and regulated systemic inflammatory diseases; however, recent findings revealed that serum levels of various adipokines correlate also with the onset and the severity of dermatological diseases. Importantly, further data confirmed that the skin serves not only as a target for adipokine signaling, but may serve as a source too. In this review, we aim to provide a complex overview on how adipokines may integrate into the (patho) physiological conditions of the skin by introducing the cell types, such as keratinocytes, fibroblasts, and sebocytes, which are known to produce adipokines as well as the signals that target them. Moreover, we discuss data from in vivo and in vitro murine and human studies as well as genetic data on how adipokines may contribute to various aspects of the homeostasis of the skin, e.g., melanogenesis, hair growth, or wound healing, just as to the pathogenesis of dermatological diseases such as psoriasis, atopic dermatitis, acne, rosacea, and melanoma.

Rosacea Is Characterized by a Profoundly Diminished Skin Barrier.

Rosacea is a common chronic inflammation of sebaceous gland-rich facial skin characterized by severe skin dryness, elevated pH, transepidermal water loss, and decreased hydration levels. Until now, there has been no thorough molecular analysis of permeability barrier alterations in the skin of patients with rosacea. Thus, we aimed to investigate the barrier alterations in papulopustular rosacea samples compared with healthy sebaceous gland-rich skin, using RNA sequencing analysis (n = 8). Pathway analyses by Cytoscape ClueGO revealed 15 significantly enriched pathways related to skin barrier formation. RT-PCR and immunohistochemistry were used to validate the pathway analyses. The results showed significant alterations in barrier components in papulopustular rosacea samples compared with sebaceous gland-rich skin, including the cornified envelope and intercellular lipid lamellae formation, desmosome and tight junction organizations, barrier alarmins, and antimicrobial peptides. Moreover, the barrier damage in papulopustular rosacea was unexpectedly similar to atopic dermatitis; this similarity was confirmed by immunofluorescent staining. In summary, besides the well-known dysregulation of immunological, vascular, and neurological functions, we demonstrated prominent permeability barrier alterations in papulopustular rosacea at the molecular level, which highlight the importance of barrier repair therapies for rosacea.

GPR119 Is a Potent Regulator of Human Sebocyte Biology.

We have shown previously that endocannabinoids promote sebaceous lipogenesis, and sebocytes are involved in the metabolism of the endocannabinoid-like substance oleoylethanolamide (OEA). OEA is an endogenous activator of GPR119, a recently deorphanized receptor, which currently is being investigated as a promising antidiabetic drug target. In this study, we investigated the effects of OEA as well as the expression and role of GPR119 in human sebocytes. We found that OEA promoted differentiation of human SZ95 sebocytes (elevated lipogenesis, enhanced granulation, and the induction of early apoptotic events), and it switched the cells to a proinflammatory phenotype (increased expression and release of several proinflammatory cytokines). Moreover, we could also demonstrate that GPR119 was expressed in human sebocytes, and its small interfering RNA-mediated gene silencing suppressed OEA-induced sebaceous lipogenesis, which was mediated via c-Jun N-terminal kinase, extracellular signal-regulated kinase 1/2, protein kinase B, and CRE-binding protein activation. Finally, our pilot data demonstrated that GPR119 was downregulated in the sebaceous glands of patients with acne, arguing that GPR119 signaling may indeed be disturbed in acne. Collectively, our findings introduce the OEA/GPR119 signaling as a positive regulator of sebocyte differentiation and highlight the possibility that dysregulation of this pathway may contribute to the development of seborrhea and acne.