Explore the vast range of titles available.

Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne. Although acne vulgaris is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here the authors show that GATA6 is involved in maintaining homeostasis of the upper pilosebaceous unit of human skin and may contribute to acne pathogenesis.

Sebum production is key in the pathophysiology of acne, an extremely common condition, which when severe, may require treatment with isotretinoin, a known teratogen. Apart from isotretinoin and hormonal therapy, no agents are available to reduce sebum. Increasing our understanding of the regulation of sebum production is a milestone in identifying alternative therapeutic targets. Studies in sebocytes and human sebaceous glands indicate that agonists of peroxisome proliferator-activated receptors (PPARs) alter sebaceous lipid production. The goal of this study is to verify the expression and activity of PPARs in human skin and SEB-1 sebocytes and to assess the effects of PPAR ligands on sebum production in patients. To investigate the contribution of each receptor subtype to sebum production, lipogenesis assays were performed in SEB-1 sebocytes that were treated with PPAR ligands and isotretinoin. Isotretinoin significantly decreased lipogenesis, while the PPARα agonist-GW7647, PPARδ agonist-GW0742, PPARα/δ agonist-GW2433, PPARγ agonist rosiglitazone, and the pan-agonist-GW4148, increased lipogenesis. Patients treated with thiazolidinediones or fibrates had significant increases in sebum production (37 and 77%, respectively) when compared to age-, disease-, and sex-matched controls. These data indicate that PPARs play a role in regulating sebum production and that selective modulation of their activity may represent a novel therapeutic strategy for the treatment of acne.

Acne vulgaris is a nearly universal cutaneous inflammatory disease. Excess sebum production is an integral part of disease pathogenesis. Medical therapies that reduce sebum excretion result in clinical improvement of acne. Given the preferential susceptibility of lipid-containing cells to cold, we investigated the hypothesis that controlled local skin cooling causes preferential injury to sebaceous glands, in murine and swine models using a range of temperatures as low as -10 °C, and then on the backs of human subjects. In mouse ears, peak histologic damage occurred 72 hours after treatment; eosinophilic necrotic plugs formed within sebaceous glands, and the number of glands was significantly reduced up to 1 week post treatment. Cooling disrupted sebocyte cell membranes, alkaline phosphatase activity, and significantly reduced sebocyte lipid content. In human volunteers, cooling damaged sebaceous glands and reduced sebum output for 2 weeks, with minimal injury to surrounding tissues. Selective cryolysis of sebaceous glands is achievable through brief, non-invasive skin cooling, suggesting that controlled cooling could be developed as an effective treatment for acne vulgaris.

PurposeTo investigate the overexpression of genes in sebaceous gland carcinoma (SGC) of the eyelid compared to sebaceous adenoma of the eyelid in order to elucidate the molecular mechanism underlying pathogenesis.MethodsWe performed histopathological examination of eyelid tissues surgically removed from four patients diagnosed with SGC (cases 1–3) and sebaceous adenoma (case 4) of the eyelid. Next, we performed global gene expression analysis of surgical tissue samples using a GeneChip® system and the Ingenuity Pathways Knowledge Base. The results of the GeneChip® analysis were explored with quantitative real-time polymerase chain reaction (qRT-PCR) analysis.ResultsIn the SGC samples, we found that 211, 199, and 199 genes, respectively, showed ≥ 2.0-fold higher expression than those in the sebaceous adenoma sample (case 4); 194 genes were common to all three SGC samples. For the 194 genes with upregulated expression, functional category analysis showed that SGC of the eyelid employed a unique gene network, including cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 1 (CDK1), and cyclin E1 (CCNE1), which are related to cell cycle progression, incidence of tumor, and cell viability. Furthermore, qRT-PCR analysis showed that the expression levels of CDKN2A, CDK1, and CCNE1 were significantly upregulated in all SGC cases compared to those in the sebaceous adenoma case. These data were similar to the results of microarray analysis.ConclusionOverexpression of cell cycle-related genes CDKN2A, CDK1, CCNE1, and their gene network may help elucidate the pathogenic pathway of SGC of the eyelid at the molecular level.

In mammalian epidermis, the level of β-catenin signaling regulates lineage selection by stem cell progeny. High levels of β-catenin stimulate formation of hair follicles, whereas low levels favor differentiation into interfollicular epidermis and sebocytes. In transgenic mouse epidermis, overexpression of β-catenin leads to formation of hair follicle tumors, whereas overexpression of N-terminally truncated Lef1, which blocks β-catenin signaling, results in spontaneous sebaceous tumors. Accompanying overexpression of β-catenin is up-regulation of Sonic hedgehog (SHH) and its receptor. Patched (PTCH/Ptch). In ΔNLef1 tumors Ptch mRNA is up-regulated in the absence of SHH. We now show that PTCH is up-regulated in both human and mouse sebaceous tumors and is accompanied by overexpression of Indian hedgehog (IHH). In normal sebaceous glands IHH is expressed in differentiated sebocytes and the transcription factor GLI1 is activated in sebocyte progenitors, suggesting a paracrine signaling mechanism. PTCH1 and IHH are up-regulated during human sebocyte differentiation in vitro and inhibition of hedgehog signaling inhibits growth and stimulates differentiation. Overexpression of ΔNLef1 up-regulates IHH and stimulates proliferation of undifferentiated sebocytes. We present a model of the interactions between β-catenin and hedgehog signaling in the epidermis in which SHH promotes proliferation of progenitors of the hair lineages whereas IHH stimulates proliferation of sebocyte precursors.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin dryness, inflammation, and itch. A major hallmark of AD is an elevation of the immune cytokines IL-4 and IL-13. These cytokines lead to skin barrier disruption and lipid abnormalities in AD, yet the underlying mechanisms are unclear. Sebaceous glands are specialized sebum-producing epithelial cells that promote skin barrier function by releasing lipids and antimicrobial proteins to the skin surface. Here, we show that in AD, IL-4 and IL-13 stimulate the expression of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), a key rate-limiting enzyme in sex steroid hormone synthesis, predominantly expressed by sebaceous glands in human skin. HSD3B1 enhances androgen production in sebocytes, and IL-4 and IL-13 drive lipid abnormalities in human sebocytes and keratinocytes through HSD3B1. Consistent with our findings in cells, HSD3B1 expression is elevated in the skin of AD patients and can be restored by treatment with the IL-4Rα monoclonal antibody, Dupilumab. Androgens are also elevated in a mouse model of AD, though the mechanism in mice remains unclear. Our findings illuminate a connection between type 2 immunity and sex steroid hormone synthesis in the skin and suggest that abnormalities in sex steroid hormone synthesis may underlie the disrupted skin barrier in AD. Furthermore, targeting sex steroid hormone synthesis pathways may be a therapeutic avenue to restoring normal skin barrier function in AD patients.

Acne vulgaris is a cutaneous chronic inflammatory disorder with complex pathogenesis. Four factors play vital roles in acne pathophysiology: hyperseborrhea and dysseborrhea, altered keratinization of the pilosebaceous duct, Cutibacterium acnes (C. acnes) and inflammation. The main hormones responsible for the development of acne vulgaris include androgens, insulin and insulin-like growth factor-1. Other factors involved in this process are corticotropin-releasing hormone, α-melanocyte-stimulating hormone and substance P. Wnt/β-catenin signaling pathway, phosphoinositide 3-kinase (PI3K)/Akt pathway, mitogen-activated protein kinase pathway, adenosine 5′-monophosphate-activated protein kinase pathway and nuclear factor kappa B pathway participate in the modulation of sebocyte, keratinocyte and inflammatory cell (e.g. lymphocytes, monocytes, macrophages, neutrophils) activity. Among all the triggers and pathways mentioned above, IGF-1-induced PI3K/Akt/Forkhead box protein O1/mammalian target of rapamycin (mTOR) C1 pathway is the most important signaling responsible for acne pathogenesis. Commonly used anti-acne agents include retinoids, benzoyl peroxide, antibiotics and hormonal agents (e.g. spironolactone, combination oral contraceptive and flutamide). New approaches including peroxisome proliferator-activated receptor γ modifier, melanocortin receptor antagonists, epigallocatechin-3-gallate, metformin, olumacostat glasaretil, stearoyl-CoA desaturase inhibitor omiganan pentahydrochloride, KDPT, afamelanotide, apremilast and biologics have been developed as promising treatments for acne vulgaris. Although these anti-acne agents have various pharmacological effects against the diverse pathogenesis of acne, all of them have a synergistic mode of action, the attenuation of Akt/mTORC1 signaling and enhancement of p53 signal transduction. In addition to drug therapy, diet with no hyperglycemic carbohydrates, no milk and dairy products is also beneficial for treatment of acne.

Sebaceous glands (SGs), essential elements of the skin barrier in sheep, are tightly regulated by the androgen signaling pathway. This study investigated how androgens influence SGs hyperplasia in sheep by combining morphological assessments with transcriptomic analysis. Histological examination revealed a significant increase ( P  < 0.05) in both the number and average size of SGs in the testosterone-treated groups across four concentration gradients compared to the control group. Transcriptome sequencing was performed on fifteen skin samples, revealing that, compared to the control group, 371 genes were upregulated and 115 were downregulated across the four treatment groups. The upregulated genes were predominantly enriched in lipid metabolism pathways, while the downregulated genes were mainly associated with keratin filament structures. Protein-protein interaction (PPI) network analysis identified ten hub genes involved in mitochondrial β-oxidation and lipid synthesis. These findings were further supported by gene set enrichment analysis (GSEA), which indicated significant activation of fatty acid metabolic pathways ( P  < 0.05). The results of this study suggest that androgens may be involved in SGs hyperplasia in sheep by regulating mitochondrial lipid metabolism-related pathways.

Leucine-rich repeats and immunoglobulin-like domains protein 1 (Lrig1) is a functional inhibitor of the epidermal growth factor receptor. Lrig1-positive stem cells are located in the isthmus region of the mouse hair follicle (HF) and are known contributors to sebaceous gland (SG) formation and homeostasis. In this study, we performed a topical tamoxifen inducible diphtheria toxin-mediated ablation of Lrig1-expressing cells in transgenic mice to investigate their function in vivo. Selective depletion of Lrig1-positive cells resulted in a complete but reversible loss of SGs, with atrophy beginning at day 14 and full recovery occurring after six months. In the absence of the Lrig1 niche, junctional-zone keratinocytes adopted an interfollicular epidermis-like phenotype (K1-positive), and repopulating cells from other epidermal compartments failed to differentiate into the sebocyte lineage. These findings demonstrate that Lrig1-positive progenitors are crucial for proper sebaceous gland morphogenesis and maintenance. Our results highlight the importance of Lrig1-positive cells in SG-related skin physiology.

Most studies on the skin focus primarily on the hair follicle and interfollicular epidermis, whereas little is known regarding the homeostasis of the sebaceous gland (SG). The SG has been proposed to be replenished by different pools of hair follicle stem cells and cells that resides in the SG base, marked by Blimp1. Here, we demonstrate that single Blimp1 + cells isolated from mice have the potential to generate SG organoids in vitro. Mimicking SG homeostasis, the outer layer of these organoids is composed of proliferating cells that migrate inward, undergo terminal differentiation and generating lipid-filled sebocytes. Performing confocal microscopy and mass-spectrometry, we report that these organoids exhibit known markers and a lipidomic profile similar to SGs in vivo. Furthermore, we identify a role for c-Myc in sebocyte proliferation and differentiation, and determine that SG organoids can serve as a platform for studying initial stages of acne vulgaris, making this a useful platform to identify potential therapeutic targets. The sebaceous gland (SG) has been proposed to be replenished by pools of cells, including a population in the SG base, marked by Blimp1. Here, the authors show that Blimp1 + cells can establish an organoid model of the SG, which is regulated by c-Myc and can recapitulate the early stages of acne vulgaris.