Experimental Dermatology最新文献

The aim of this study is to identify the key biomarker of keloid (KD) with significant diagnostic value and to construct the related competing endogenous RNA (ceRNA) network and disease diagnostic model to provide new ideas for the early diagnosis and prevention of KD. Public databases were used to identify the key gene of KD. Enrichment analysis and immune cell infiltration (ICI) analysis revealed its functional and immune characteristics. Then, a ceRNA network was constructed to explore the potential pathways of it. Random forest (RF) analysis was applied to construct a predictive model for the disease diagnosis of KD. Finally, immunohistochemistry (IHC) and RT-qPCR were used to verify the differential expression of key gene. ERRFI1 was identified as a key biomarker in KD and was lowly expressed in KD. The ceRNA network revealed that H0TAIRM1-has-miR-148a-3p-ERRFI1 may be a potential pathway in KD. Finally, a 2-gene diagnostic prediction model (ERRFI1, HSD3B7) was constructed and externally validated and the results suggested that the model had good diagnostic performance. ERRFI1 is a downregulated gene in KD and is expected to be a promising predictive marker and disease diagnostic gene. ICI may play a role in the progression of KD. The ceRNA network may provide new clues to the potential pathogenesis of KD. Finally, the new KD diagnostic model could be an effective tool for assessing the risk of KD development.

Platelet-activating factor (PAF) is an important chemical mediator in the field of inflammation, but its function in the skin is unclear. To unravel the role of PAF, we focused on lysophosphatidylcholine acyltransferase 2 (LPCAT2 also called LPLAT9), a biosynthetic enzyme involved in PAF production, and investigated the role of PAF in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). We measured the amount of PAF in the skin and investigated the ear swelling responses and leukocyte infiltration into the skin following the application of 2,4,6-trinitro-1-chlorobenzene (TNCB) or croton oil in wild-type (WT) and LPCAT2 knockout (LPCAT2-KO) mice. The amount of PAF was increased in the skin of WT mice after TNCB or croton oil application but not detected in LPCAT2-KO mice. The ear swelling response was decreased in LPCAT2-KO mice compared with that in WT mice. In the ACD model, the numbers of lymphocytes, eosinophils, macrophages, mast cells and neutrophils were smaller in LPCAT2-KO mice than in WT mice. In the ICD model, the ear swelling response was also decreased in LPCAT2-KO mice compared with that in WT mice. When double staining of each inflammatory cell type and LPCAT2 was performed in ACD tissue, marked co-staining of the eosinophil marker and LPCAT2 was observed. In addition, LPCAT2 expression was observed in the epidermis. These results indicate that PAF is involved in the infiltration of several cell types into the sites of allergic and non-allergic skin inflammation. Furthermore, eosinophils and keratinocytes are primarily responsible for PAF production in skin inflammation.

Keloid scarring is a complex fibroproliferative disorder characterised by excessive fibroblast proliferation. Inhibition of cellular glycolysis effectively suppresses the proliferation of keloid fibroblasts (KFs). Neural precursor cell-expressed developmentally downregulated gene 4-like (NEDD4L), a ubiquitin ligase, regulates cell proliferation in different diseases. This study investigated the effects of NEDD4L on glucose metabolism, proliferation and migration in KFs. Primary KFs were isolated from keloid skin tissues obtained from patients with active-stage keloids. Cell transfection was used to upregulate or downregulate NEDD4L and Yin Yang 1 (YY1) in KFs. Protein expression was assessed by immunohistochemistry and western blotting. The viability, proliferative capacity and migration ability of KFs were evaluated using the MTT method and the EdU and wound healing assays, respectively. The regulatory effect of NEDD4L on YY1 ubiquitination was examined by coimmunoprecipitation. The interaction between YY1 and hexokinase 2 (HK2) was confirmed by a dual-luciferase reporter assay. NEDD4L was downregulated, whereas YY1 and HK2 were highly expressed in keloid tissues compared with normal skin. Overexpression of NEDD4L inhibited the proliferation and migration of KFs. NEDD4L promoted YY1 degradation in KFs by inducing its ubiquitination. Upregulation of YY1 induced glucose consumption and lactate production in KFs via the transcriptional regulation of HK2. Increased expression of YY1 reversed the reduced viability, proliferation, and migration of KFs overexpressing NEDD4L. YY1 also reversed the NEDD4L-induced inhibition of glucose consumption and lactate production in KFs. Additionally, an in vivo study confirmed the inhibitory roles of NEDD4L overexpression and YY1 knockdown in keloid formation. NEDD4L suppressed the viability, proliferation and migration of KFs by regulating YY1 ubiquitination-mediated glycolysis through HK2. These findings suggest a novel regulatory axis, NEDD4L/YY1/HK2, that mediates glucose metabolism in keloid formation.

Drug reactions with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse hypersensitivity reactions with distinct clinical manifestations. Regulatory T (Treg) cells may behave differently in these syndromes, contributing to their diverse clinical features and outcomes. This study compared Treg dynamics between DRESS and SJS/TEN patients during the acute and recovery phases. Flow cytometry quantitatively analysed and defined the immunophenotype of CD4⁺CD25⁺CD127⁻FoxP3⁺ Tregs in blood from DRESS and SJS/TEN patients indicated that Treg percentages were lowest in DRESS patients during the acute phase compared to those in the recovery phase in DRESS patients and the acute phase in SJS/TEN patients. During the acute phase, CTLA-4 expression in Tregs in both DRESS patients with and without autoimmune sequelae was significantly increased, while only DRESS patients without autoimmune sequelae had elevated OX40 expression compared to the healthy controls. High IL-10 expression in Tregs during the acute phase in SJS/TEN patients was also observed. The suppressive function of Tregs was lower in DRESS compared to SJS/TEN, which was determined using a suppression assay by co-culturing autologous Treg and effector T cells. Furthermore, NanoString technology explored mRNA profiles in Tregs. Genes associated with the JAK/STAT pathway were found to be downregulated during the acute phase in DRESS patients who later developed autoimmune sequelae. Our findings evidenced impaired Treg function in DRESS compared to SJS/TEN. The early disturbance of the JAK/STAT pathway may serve as a prognostic marker for autoimmune development in DRESS patients.

Dupilumab, an anti-interleukin (IL)-4 receptor α-antibody, was approved in 2018 for the treatment of moderate-to-severe atopic dermatitis (AD) in Japan. Although real-world data have accumulated on the effectiveness and safety of dupilumab in patients with AD in the short term, real-world data on its long-term use are limited. In this study, we retrospectively investigated its effectiveness, safety and laboratory data in patients with AD who received dupilumab for 3 years. All adult patients with moderate-to-severe AD who were administered dupilumab between June 2018 and December 2020 and were treated with dupilumab for more than 3 years were included in this study. Sixty Japanese patients with AD (male, 48; female, 12) were included in this study. Their mean age was 36.6 ± 11.0 (standard deviation) years. The mean Eczema Area and Severity Index (EASI) was 29.9 ± 9.2. The clinical severity scales, including Investigator's Global Assessment (IGA), EASI and affected body surface area (BSA), and patient-reported outcomes, such as Dermatology Quality Life Index (DLQI), Patient-Oriented Eczema Measure (POEM) and visual analogue scale (VAS) of pruritus, significantly improved at 3 months, and at 1, 2 and 3 years after initiating dupilumab. The total EASI score significantly decreased by a mean of 66.8% at 3 months, 81.0% at 1 year, 85.3% at 2 years and 90.0% at 3 years after initiating dupilumab. The serum levels of thymus and activation-regulated chemokine (TARC), immunoglobulin E (IgE) and lactate dehydrogenase (LDH) significantly decreased at 1, 2 and 3 years. A slight decrease in circulating neutrophils was observed in patients with AD treated with dupilumab over periods from 3 months to 3 years. The number of circulating eosinophils significantly decreased at 2 and 3 years after initiating dupilumab. The most common adverse event was ocular disorders observed in 23 patients (38.3%). Our study shows the sustained effectiveness and tolerable safety of 3-year usage of dupilumab in Japanese patients with atopic dermatitis. Furthermore, dupilumab decreased neutrophil values at 3 months and later, and reduced the number of circulating eosinophils after long-term use (≧ 2 years).