Particulate matter (PM) increases levels of pro-inflammatory cytokines, but its effects on the skin remain largely unknown. We investigated the signal transduction pathway and epigenetic regulatory mechanisms underlying cellular inflammation induced by PM with a diameter of ≤ 2.5 (PM2.5) in vitro and in vivo. PM2.5-treated skin keratinocytes produced various inflammatory cytokines, including IL-6. The binding of PM2.5 to TLR5 initiated intracellular signaling through MyD88, and led to the translocation of NFκB to the nucleus, where it bound the NFκB site within IL-6 promoter. Furthermore, PM2.5 induced a direct interaction between TLR5 and NOX4, and in turn induced the production of ROS and activated NFκB-IL-6 downstream, which was prevented by siRNA-mediated knockdown of NOX4 or antioxidant treatment. Furthermore, expression of TLR5, MyD88, NOX4, phospho-NFκB, and IL-6 was increased in skin tissue of PM2.5-treated flaky tail mice. PM2.5-induced increased transcription of IL-6 was regulated via DNA methylation and histone methylation by epigenetic modification; the binding of DNA demethylase and histone methyltransferase to the IL-6 promoter regions resulted in increased IL-6 mRNA expression. Our findings provide deep insight into the pathogenesis of PM2.5 exposure and can be used as a therapeutic strategy to treat inflammatory skin diseases caused by PM2.5 exposure.

Recently, thymic stromal lymphopoietin (TSLP), which is well studied in allergic diseases, has been reported in fibrotic diseases, including idiopathic pulmonary fibrosis and atopic dermatitis fibrosis. However, the role of TSLP in keloid is obscure. In this study, we assessed the expression of TSLP in keloid tissue and investigated the possible role of TSLP in keloid pathogenesis. We observed that TSLP expression was increased in keloid tissue compared to normal tissue. Furthermore, TSLP treatment induced increased collagen I and collagen III expression in fibroblasts via transforming growth factor-?; however, there was higher expression in keloid fibroblasts compared to normal fibroblasts. Stromal cell-derived factor-1?, which was recently reported to enhance wound healing through recruiting bone marrow-derived mesenchymal stem cells to the wound area, increased after TSLP treatment in fibroblasts and was primarily expressed in ?-smooth muscle action-positive myofibroblasts in keloid tissue. Furthermore, fibrocytes expressing CXCR4, a stromal cell-derived factor-1? receptor, were significantly increased in keloid tissue compared to normal tissue. Finally, intradermal TSLP injection on BALB/c mice increased stromal cell-derived factor-1? expression and CXCR4(+) fibrocytes infiltration. Our data suggest that TSLP is a potent inducer of collagen and transforming growth factor-? production in keloid fibroblasts. In addition, it might activate the CXCR4/stromal cell-derived factor-1 axis to increase fibrocyte infiltration into the keloid tissue.

Background Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by defective skin barrier and Th2 immune responses. Chitinase 3‐like 1 (CHI3L1), also known as breast regression protein 39 (BRP‐39) in mice and human homologue YKL‐40, plays important roles in Th2 inflammation and allergen sensitization. CHI3L1 has been implicated in a variety of diseases including asthma characterized by inflammation, apoptosis and tissue remodelling, but its role in AD remains elusive. Objective The aim of this study was to investigate the role of CHI3L1 in the development and progression of AD. Results We investigated YKL‐40 levels in the serum and skin of AD patients by ELISA and immunofluorescence, respectively. Using a murine model of AD induced by ovalbumin (OVA), we investigated Th2 immune responses, M2 macrophage activation and skin barrier gene expression using wild‐type (WT) and BRP‐39 null mutant (BRP‐39−/−) mice. YKL‐40 level was significantly increased in serum of AD patients. In addition, both mRNA and protein expression levels of BRP‐39 were higher in OVA‐sensitized WT mice than in control mice. OVA‐sensitized BRP‐39−/− mice showed decreased epidermal thickness, lower total serum IgE, Th2 cytokine levels and CD4+ effector T cell populations than OVA‐sensitized WT mice. Induction of BRP‐39 was dominant in dermal macrophages. BRP‐39 deficiency was found to be involved in M2 macrophage activation. Consistently, the YKL‐40 level in the skin of AD patients was higher than in normal subjects and it was expressed in dermal macrophages. BRP‐39 deficiency attenuated dysregulation of skin barrier and tight junction genes. Conclusions and Clinical Relevance These findings demonstrate that CHI3L1 mediates the development of AD induced by OVA, affecting Th2 inflammation, M2 macrophage activation and skin barrier function.

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Adipokines modulate immune responses and lipid metabolism in allergic disease; however, little is known about their role in the skin barrier and atopic dermatitis (AD). We identified ZAG, an adipokine that regulates lipid mobilization, as a biomarker for AD. ZAG levels were consistently decreased in sera, T cells, and skin in human AD patients compared with healthy controls. ZAG was primarily detected in the stratum corneum along with FLG and LOR. Knockdown of ZAG with short hairpin RNA resulted in decreased FLG and increased TSLP. Topical ZAG treatment in AD mice recovered ZAG expression in the skin and improved AD-like symptoms, transepidermal water loss, and ceramide levels. Furthermore, topical ZAG treatment induced immunoregulatory effects, including reduction of IL-4, IL-17, and IFN-g and increased Foxp3 in the skin and lymphoid organs. Interestingly, ZAG treatment also recovered decreased levels of ADAM17, an important player in skin barrier function and immune response in AD. Thus, ZAG deficiency is closely related to skin barrier function and the immune abnormalities of AD, and we suggest that restoration of ZAG may be a promising therapeutic option for the treatment of AD.

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Background While the incidence of patients with atopic dermatitis (AD) with atopic march (AM) showing respiratory allergy is steadily rising, the pathomechanism is still unknown. There are currently no biomarkers to predict progression of AM. Methods To explore the mechanism of AM, patients with AD and AM and healthy controls were recruited and RNA microarray, flow cytometry, quantitative real-time polymerase chain reaction, and immunofluorescence staining were performed. We also co-cultured dendritic cells and CD4 + T cells with various Dermatophagoides farinae allergen fractions. Cytokine levels were evaluated using enzyme-linked immunosorbent assay. Findings Both fatty-acid-binding protein 5 (FABP5) and Th17-related genes were more highly expressed in AM. FABP5 knockdown significantly decreased Th17-inducing cytokines in keratinocytes and IL-17A in T cells from AM patients. Further confirmation was obtained using an AM mice model compared to mice without AM. Der f 1, a major D. farinae allergen, increased FABP5 and IL-17A expression in T cells from AM patients. Higher serum FABP5 levels from AM patients were positively correlated with serum IL-17A levels. Interpretation FABP5 expression, possibly enhanced by higher epicutaneous and respiratory sensitization to Der f 1, may directly promote Th17 responses in AD patients with AM. Thus, AM progression can be explained by Th17 reaction induced by FABP5. FABP5 was identified as a potential biomarker in AM. Funding This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT; No. NRF-2017R1A2B4009568), grants of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, and the Republic of Korea (HI13C0010, HI14C1324, HI14C1799).

Introduction & objectivesHead and neck dermatitis (HND) is a refractory phenotype of atopic dermatitis (AD) and can be a therapeutic challenge due to lack of responsiveness to conventional treatments. Previous studies have suggested that the microbiome and fungiome may play a role in inducing HND, but the underlying pathogenic mechanisms remain unknown. This study aimed to determine the link between HND and fungiome and to examine the contribution of Malassezia furfur.Materials and methodsTo identify the effect of the sensitization status of M. furfur on HND, 312 patients diagnosed with AD were enrolled. To elucidate the mechanism underlying the effects of M. furfur, human keratinocytes and dermal endothelial cells were cultured with M. furfur and treated with Th2 cytokines. The downstream effects of various cytokines, including inflammation and angiogenesis, were investigated by real-time quantitative PCR. To identify the association between changes in lipid composition and M. furfur sensitization status, D-squame tape stripping was performed. Lipid composition was evaluated by focusing on ceramide species using liquid chromatography coupled with tandem mass spectrometry.ResultsIncreased sensitization to M. furfur was observed in patients with HND. Additionally, sensitization to M. furfur was associated with increased disease severity in these patients. IL-4 treated human keratinocytes cultured with M. furfur produced significantly more VEGF, VEGFR, IL-31, and IL-33. IL-4/M. furfur co-cultured dermal endothelial cells exhibited significantly elevated VEGFR, TGF-β, TNF-α, and IL-1β levels. Stratum corneum lipid analysis revealed decreased levels of esterified omega-hydroxyacyl-sphingosine, indicating skin barrier dysfunction in HND. Finally, M. furfur growth was inhibited by the addition of these ceramides to culture media, while the growth of other microbiota, including Cutibacterium acnes, were not inhibited.ConclusionsUnder decreased levels of ceramide in AD patients with HND, M. furfur would proliferate, which may enhance pro-inflammatory cytokine levels, angiogenesis, and tissue remodeling. Thus, it plays a central role in the pathogenesis of HND in AD.