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The cumulative effect of compound heterozygous variants in TRPV3 caused Olmsted syndrome. TRPV3复合杂合变体的累积效应导致了奥姆斯特综合征。
IF 4.6 Pub Date : 2024-11-05 DOI: 10.1016/j.jdermsci.2024.10.005
Ran Mo, Xiaoqi Ma, Linghan Hu, Yingjian Tan, Lei Qiang, Yong Yang, Xiaoping Wang, Zhiming Chen

Background: Olmsted syndrome (OS) is a rare genodermatosis predominantly inherited in an autosomal dominant manner, typically arising from gain-of-function (GOF) variants in the transient receptor potential channel vanilloid 3 (TRPV3) gene.

Objective: This study aims to investigate potential mechanisms underlying OS in two cases presenting with an autosomal recessive inheritance pattern.

Methods: Next-generation sequencing panel was employed to identify TRPV3 variants. TRPV3 plasmids carrying specific point variations were generated and transiently transfected into HEK293T cells. Electrophysiological patch-clamp techniques were utilized to record voltage-activated and ligand-activated currents. Celltiter-Glo luminescent assay was employed to analyze the cell viabilities.

Results: Compound heterozygous variants, c.1563 G>C (p.W521C) and c.1376 C>T (p.S459L), as well as c.1773 G>C (p.L591F) and c.2186 G>A (p.R729Q), were identified in the two OS patients respectively. Electrophysiological analysis of ligand-induced activation of TRPV3 variants demonstrated the closest correlation with clinical manifestations. All four variants displayed GOF channel activity characterized by increased sensitivity. Notably, W521C and L591F exhibited both heightened sensitivity and lower EC50 values for the TRPV3 agonist. Co-transfection with wild-type TRPV3 plasmids significantly rescued these effects. Cells co-transfected with the corresponding compound heterozygous variants exhibited intermediate electrophysiological characteristics.

Conclusions: In this study, we present two cases of OS by autosomal-recessive inheritance of TPRV3 variants. This study presents a notable observation of compound heterozygous GOF variants in TRPV3, highlighting their cumulative impact on clinical manifestations. Additionally, we advocate for the use of ligand-dependent ion channel activity assays to assess the pathogenicity of TRPV3 variants in OS.

背景:奥姆斯特德综合征(OS)是一种罕见的遗传性皮肤病,主要为常染色体显性遗传,通常由瞬时受体电位通道香草素3(TRPV3)基因的功能增益(GOF)变异引起:本研究旨在调查两例常染色体隐性遗传病例中 OS 的潜在发病机制:方法:采用下一代测序面板鉴定TRPV3变体。生成携带特定点变异的TRPV3质粒,并将其瞬时转染到HEK293T细胞中。利用电生理膜片钳技术记录电压激活电流和配体激活电流。Celltiter-Glo 发光试验用于分析细胞活力:结果:在两名 OS 患者中分别发现了 c.1563 G>C (p.W521C) 和 c.1376 C>T (p.S459L),以及 c.1773 G>C (p.L591F) 和 c.2186 G>A (p.R729Q)的复合杂合变异。对配体诱导激活的 TRPV3 变体进行的电生理分析表明,它们与临床表现的相关性最为密切。所有四个变体都显示出以敏感性增加为特征的 GOF 通道活性。值得注意的是,W521C 和 L591F 对 TRPV3 激动剂的敏感性提高,EC50 值降低。与野生型 TRPV3 质粒共转染可显著缓解这些影响。与相应的复合杂合变体共转染的细胞表现出中间电生理特征:在这项研究中,我们发现了两例因 TPRV3 变异而导致常染色体隐性遗传的 OS 病例。本研究对TRPV3的复合杂合GOF变异进行了显著观察,强调了它们对临床表现的累积性影响。此外,我们主张使用配体依赖性离子通道活性测定法来评估TRPV3变体在OS中的致病性。
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引用次数: 0
The decrease in peripheral blood basophils in a mouse model of IgE-induced inflammation involves their migration to lymph nodes 在 IgE 诱导的炎症小鼠模型中,外周血嗜碱性粒细胞的减少涉及它们向淋巴结的迁移。
IF 4.6 Pub Date : 2024-11-01 DOI: 10.1016/j.jdermsci.2024.09.004
Ni Ma , Izumi Kishimoto , Aki Tajima , Noriko Kume , Naotomo Kambe , Hideaki Tanizaki

Background

During the active phase of urticaria, a decrease in peripheral blood basophils, known as basopenia, is observed. We previously reported that basopenia occurs as a result of basophils migrating to the skin in a contact dermatitis model where a Th2 response is induced with oxazolone.

Objective

Although there is currently no established model for urticaria, given that urticaria is an IgE-mediated immediate-type allergic reaction, we aimed to determine whether an IgE-mediated model could reproduce the decrease in basophils in peripheral blood observed during the active phase of urticaria.

Methods

Mice were pretreated with 2,4,6-trinitrophenylhaptene (TNP)-specific IgE and basophil dynamics were examined following stimulation with TNP-ovalbumin. Mast cell-deficient WBB6F1-KitW/KitW-v mice were used to investigate the role of mast cells in this IgE-mediated model.

Results

Following stimulation, we observed immediate ear swelling and basopenia after 0.5 hours. However, the number of basophils observed in the skin lesions was low, while a higher number of basophils were observed in the antigen-draining lymph nodes (LN). In mast cell-deficient mice, no increase in basophils in the LN was observed, reflecting reduced antigen influx into the LN, but basophils remained in the skin.

Conclusions

In the IgE-mediated mouse model, basopenia was observed, which coincided with the induction of inflammation in the skin. The migration of basophils to the LN in this model suggests that the systemic immune system, including the LN, should be considered when exploring the pathogenesis of urticaria in humans.
背景:在荨麻疹的活动期,可观察到外周血嗜碱性粒细胞减少,即嗜碱性粒细胞减少症。我们以前曾报道过,在接触性皮炎模型中,嗜碱性粒细胞迁移到皮肤会导致嗜碱性粒细胞减少:尽管目前还没有荨麻疹的成熟模型,但鉴于荨麻疹是一种 IgE 介导的即时型过敏反应,我们旨在确定 IgE 介导的模型是否能重现荨麻疹活动期观察到的外周血嗜碱性粒细胞减少的现象:方法:用 2,4,6-三硝基苯基硫醇(TNP)特异性 IgE 对小鼠进行预处理,并在 TNP-ovalbumin 刺激后检测嗜碱性粒细胞的动态变化。使用肥大细胞缺陷的 WBB6F1-KitW/KitW-v 小鼠来研究肥大细胞在这种 IgE 介导的模型中的作用:结果:刺激后,我们观察到耳朵立即肿胀,并在 0.5 小时后出现嗜碱性粒细胞减少。然而,在皮肤病变中观察到的嗜碱性粒细胞数量较少,而在抗原引流淋巴结(LN)中观察到的嗜碱性粒细胞数量较多。在肥大细胞缺陷的小鼠中,淋巴结中的嗜碱性粒细胞没有增加,这反映了流入淋巴结的抗原减少,但皮肤中仍有嗜碱性粒细胞:结论:在 IgE 介导的小鼠模型中,观察到嗜碱性粒细胞减少,这与皮肤炎症的诱导相吻合。该模型中嗜碱性粒细胞向LN的迁移表明,在探索人类荨麻疹的发病机制时,应考虑包括LN在内的全身免疫系统。
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引用次数: 0
Downregulation of carnitine acetyltransferase by promoter hypermethylation regulates ultraviolet-induced matrix metalloproteinase-1 expression in human dermal fibroblasts 启动子超甲基化对肉碱乙酰转移酶的下调调节了紫外线诱导的人真皮成纤维细胞中基质金属蛋白酶-1的表达。
IF 4.6 Pub Date : 2024-11-01 DOI: 10.1016/j.jdermsci.2024.09.005
Min Ji Song , Min-Kyoung Kim , Chi-Hyun Park , Haesoo Kim , Si Hyung Lee , Dong Hun Lee , Jin Ho Chung

Background

Overexposure to ultraviolet (UV) radiation accelerates skin aging, resulting in wrinkle formation, reduced skin elasticity, and hyperpigmentation. UV irradiation induces increased matrix metalloproteinases (MMPs) that degrade collagen in the extracellular matrix. Skin aging is also accompanied by epigenetic alterations such as promoter methylation by DNA methyltransferases, leading to the activation or suppression of gene expression. Although carnitine acetyltransferase (CRAT) is implicated in aging, the effect of UV on the expression of CRAT and regulatory mechanisms of UV-induced MMP-1 expression remain unknown.

Objective

We investigated changes in CRAT expression upon UV irradiation and its effect on MMP-1 expression.

Methods

Primary human dermal fibroblasts were UV irradiated with either control or 5-AZA-dC. CRAT knockdown or overexpression was performed to investigate its effect on MMP-1 expression. The mRNA level was analyzed by quantitative real-time PCR, and protein level by western blotting.

Results

The expression of CRAT was decreased in UV-irradiated human skin in vivo and in human dermal fibroblasts in vitro. CRAT was downregulated upon UV irradiation by hypermethylation, and treatment with 5-Aza-2′-deoxycytidine, a DNA methyltransferase inhibitor, reversed UV-induced downregulation of CRAT. CRAT knockdown activated the JNK, ERK, and p38 MAPK signaling pathways, which increased MMP-1 expression. Stable overexpression of CRAT alleviated UV-induced MMP-1 induction.

Conclusion

CRAT downregulation caused by promoter hypermethylation may play an important role in UV-induced skin aging via upregulation of MMP-1 expression.
背景:过度暴露于紫外线(UV)辐射会加速皮肤老化,导致皱纹形成、皮肤弹性降低和色素沉着。紫外线照射会诱导基质金属蛋白酶(MMPs)增加,从而降解细胞外基质中的胶原蛋白。皮肤老化还伴随着表观遗传学的改变,如 DNA 甲基转移酶导致启动子甲基化,从而激活或抑制基因表达。虽然肉碱乙酰转移酶(CRAT)与衰老有关,但紫外线对 CRAT 表达的影响以及紫外线诱导 MMP-1 表达的调控机制仍不清楚:我们研究了紫外线照射时 CRAT 表达的变化及其对 MMP-1 表达的影响:方法:用对照组或 5-AZA-dC 对原代人真皮成纤维细胞进行紫外线照射。方法:用对照组或 5-AZA-dC 对原代人真皮成纤维细胞进行紫外线照射,敲除或过表达 CRAT,以研究其对 MMP-1 表达的影响。mRNA水平通过实时定量PCR分析,蛋白水平通过Western印迹分析:结果:CRAT在体内紫外线照射的人类皮肤和体外人类真皮成纤维细胞中的表达均下降。用 DNA 甲基转移酶抑制剂 5-Aza-2'-deoxycytidine 处理可逆转紫外线诱导的 CRAT 下调。CRAT 下调激活了 JNK、ERK 和 p38 MAPK 信号通路,从而增加了 MMP-1 的表达。稳定过表达 CRAT 可减轻紫外线诱导的 MMP-1 诱导:结论:启动子高甲基化导致的CRAT下调可能通过上调MMP-1的表达在紫外线诱导的皮肤老化中扮演重要角色。
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引用次数: 0
Genome-wide DNA methylation regulated by AHCY through SAM / SAH axis promotes psoriasis pathogenesis. 由 AHCY 通过 SAM / SAH 轴调节的全基因组 DNA 甲基化促进了牛皮癣的发病。
IF 4.6 Pub Date : 2024-10-31 DOI: 10.1016/j.jdermsci.2024.10.004
Lingxi Liu, Lihao Chen, Yu Hu, Qian Zhang, Kun Chen, Jiaan Zhang

Background: Psoriasis is a chronic inflammatory skin disease that affects a significant proportion of the global population. The involvement of S-adenosine homocysteine hydrolase (AHCY) in psoriasis and its impact on DNA methylation have not been extensively studied.

Objective: This study aimed to investigate the role of AHCY and its impact on DNA methylation in psoriasis pathogenesis.

Methods: In the present study, we investigated the expression of AHCY in psoriatic lesions and assessed its association with the severity of the disease. Moreover, knockdown experiments were conducted to elucidate the impact of AHCY on psoriatic symptoms, keratinocyte proliferation, and aberrant differentiation. Furthermore, alterations in DNA methylation patterns resulting from AHCY knockdown were analyzed.

Results: Our findings revealed that AHCY was upregulated in psoriatic lesions and exhibited a positive correlation with disease severity. Knockdown of AHCY alleviated psoriatic symptoms, inhibited keratinocyte proliferation, and prevented abnormal differentiation. Moreover, AHCY knockdown led to reduced levels of DNA methylation and alterations in methylation patterns. Notably, differential methylation was observed at specific gene loci associated with psoriasis-related inflammation.

Conclusion: This study highlights the potential role of AHCY in psoriasis development through its influence on DNA methylation. The findings underscore the complex interaction among AHCY, epigenetic modifications, and inflammation in the pathogenesis of psoriasis. Consequently, AHCY may serve as a promising therapeutic target for psoriasis treatment.

背景:银屑病是一种慢性炎症性皮肤病,影响着全球很大一部分人口。S-腺苷同型半胱氨酸水解酶(AHCY)参与银屑病的发病及其对DNA甲基化的影响尚未得到广泛研究:本研究旨在探讨 AHCY 在银屑病发病机制中的作用及其对 DNA 甲基化的影响:本研究调查了 AHCY 在银屑病皮损中的表达,并评估了其与银屑病严重程度的关系。此外,我们还进行了基因敲除实验,以阐明 AHCY 对银屑病症状、角质细胞增殖和异常分化的影响。此外,还分析了 AHCY 基因敲除导致的 DNA 甲基化模式的改变:我们的研究结果表明,AHCY在银屑病皮损中上调,并与疾病严重程度呈正相关。敲除 AHCY 可减轻银屑病症状,抑制角朊细胞增殖,防止异常分化。此外,AHCY基因敲除导致DNA甲基化水平降低和甲基化模式改变。值得注意的是,在与牛皮癣相关炎症有关的特定基因位点上观察到了不同的甲基化:本研究强调了 AHCY 通过影响 DNA 甲基化在银屑病发病过程中的潜在作用。研究结果强调了 AHCY、表观遗传修饰和炎症在银屑病发病机制中的复杂相互作用。因此,AHCY可能是治疗银屑病的一个有希望的靶点。
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引用次数: 0
A carbamazepine metabolite activates NLRP3 and controls skin homing of CD8+ T-cells in SJS/TEN. 一种卡马西平代谢物可激活 NLRP3 并控制 SJS/TEN 中 CD8+ T 细胞的皮肤归巢。
IF 4.6 Pub Date : 2024-10-22 DOI: 10.1016/j.jdermsci.2024.10.003
Chen Zhang, Pei Qiao, JieYu Zhang, YiXin Luo, ChunYing Xiao, ShengXian Shen, Akio Hasegawa, HongJiang Qiao, Gang Wang, Riichiro Abe, Meng Fu

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reactions with extensive keratinocyte death. Carbamazepine (CBZ), the most commonly implicated drug in SJS/TEN, is metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) into carbamazepine-10,11-epoxide (CBZE) in the liver. While CD8+ cytotoxic T cells play an important role in SJS/TEN, the underlying mechanism of exuberant immune response by CD8+ T cells in these conditions remains incompletely understood.

Objectives: To examine the expression of NLRP3 inflammasome and their skin migration in CBZE-induced SJS/TEN.

Methods: The expression of the NLRP3 inflammasome complex in skin lesions, sera, and blister fluids of SJS/TEN patients were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay. NLRP3 formation and CD8+ T cell activation status and their functions were examined by immunoblotting, immunofluorescence, and chemotaxis assays.

Results: The expression of the NLRP3 inflammasome complex was greatly increased in skin lesions of SJS/TEN patients. Moreover, IL-1β and IL-18 levels in sera and blister fluids of SJS/TEN patients were approximately 3-fold higher than those in healthy individuals, with a linear correlation between IL-1β levels and disease activity. CBZE induced NLRP3 inflammasome formation, upregulated CXCL9/CXCL10 levels, and activated CD8+ cytotoxic T cell functions via IL-1β/IL-1R or IL-18/IL-18R signaling in SJS/TEN keratinocytes, which promoted CD8+ cytotoxic T cell migration in SJS/TEN patients.

Conclusion: This study showed that CBZE promoted NLRP3 inflammasome formation and strengthened the activation and function of CD8+ cytotoxic T cells in the skin, which contributed to the initiation and progression of SJS/TEN.

背景:史蒂文斯-约翰逊综合征(SJS)和中毒性表皮坏死(TEN)是严重的药物不良反应,会导致大量角质细胞死亡。卡马西平(CBZ)是 SJS/TEN 最常涉及的药物,它在肝脏中被细胞色素 P450 酶 3A4 (CYP3A4)代谢为卡马西平-10,11-环氧化物(CBZE)。虽然CD8+细胞毒性T细胞在SJS/TEN中发挥着重要作用,但CD8+T细胞在这些病症中产生旺盛免疫反应的内在机制仍不完全清楚:研究CBZE诱导的SJS/TEN中NLRP3炎性体的表达及其皮肤迁移:方法:通过免疫组化和酶联免疫吸附试验分析SJS/TEN患者皮损、血清和水疱液中NLRP3炎性体复合物的表达。免疫印迹、免疫荧光和趋化试验检测了 NLRP3 的形成和 CD8+ T 细胞的活化状态及其功能:结果:SJS/TEN 患者皮损中 NLRP3 炎性体复合物的表达大大增加。此外,SJS/TEN 患者血清和水疱液中的 IL-1β 和 IL-18 水平约为健康人的 3 倍,IL-1β 水平与疾病活动呈线性相关。CBZE诱导NLRP3炎性体形成,上调CXCL9/CXCL10水平,并通过IL-1β/IL-1R或IL-18/IL-18R信号激活SJS/TEN角朊细胞中CD8+细胞毒性T细胞功能,从而促进SJS/TEN患者CD8+细胞毒性T细胞迁移:本研究表明,CBZE促进了NLRP3炎性体的形成,增强了皮肤中CD8+细胞毒性T细胞的活化和功能,从而导致了SJS/TEN的发生和发展。
{"title":"A carbamazepine metabolite activates NLRP3 and controls skin homing of CD8<sup>+</sup> T-cells in SJS/TEN.","authors":"Chen Zhang, Pei Qiao, JieYu Zhang, YiXin Luo, ChunYing Xiao, ShengXian Shen, Akio Hasegawa, HongJiang Qiao, Gang Wang, Riichiro Abe, Meng Fu","doi":"10.1016/j.jdermsci.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.jdermsci.2024.10.003","url":null,"abstract":"<p><strong>Background: </strong>Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reactions with extensive keratinocyte death. Carbamazepine (CBZ), the most commonly implicated drug in SJS/TEN, is metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) into carbamazepine-10,11-epoxide (CBZE) in the liver. While CD8<sup>+</sup> cytotoxic T cells play an important role in SJS/TEN, the underlying mechanism of exuberant immune response by CD8<sup>+</sup> T cells in these conditions remains incompletely understood.</p><p><strong>Objectives: </strong>To examine the expression of NLRP3 inflammasome and their skin migration in CBZE-induced SJS/TEN.</p><p><strong>Methods: </strong>The expression of the NLRP3 inflammasome complex in skin lesions, sera, and blister fluids of SJS/TEN patients were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay. NLRP3 formation and CD8<sup>+</sup> T cell activation status and their functions were examined by immunoblotting, immunofluorescence, and chemotaxis assays.</p><p><strong>Results: </strong>The expression of the NLRP3 inflammasome complex was greatly increased in skin lesions of SJS/TEN patients. Moreover, IL-1β and IL-18 levels in sera and blister fluids of SJS/TEN patients were approximately 3-fold higher than those in healthy individuals, with a linear correlation between IL-1β levels and disease activity. CBZE induced NLRP3 inflammasome formation, upregulated CXCL9/CXCL10 levels, and activated CD8<sup>+</sup> cytotoxic T cell functions via IL-1β/IL-1R or IL-18/IL-18R signaling in SJS/TEN keratinocytes, which promoted CD8<sup>+</sup> cytotoxic T cell migration in SJS/TEN patients.</p><p><strong>Conclusion: </strong>This study showed that CBZE promoted NLRP3 inflammasome formation and strengthened the activation and function of CD8<sup>+</sup> cytotoxic T cells in the skin, which contributed to the initiation and progression of SJS/TEN.</p>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
P2X7R-primed keratinocytes are susceptible to apoptosis via GPCR-Gβγ-pERK signal pathways. P2X7R刺激的角质形成细胞易通过GPCR-Gβγ-pERK信号通路发生凋亡。
IF 4.6 Pub Date : 2024-10-06 DOI: 10.1016/j.jdermsci.2024.10.001
Tomoki Nishiguchi, Haruna Kimura, Yuki Saito, Takeaki Ozawa, Riichiro Abe, Akito Hasegawa

Background: Cell death constitutes a pivotal biological phenomenon essential for the preservation of homeostasis within living organisms. In the context of maintaining a functional skin barrier, keratinocytes exert positively and negatively control cell death signals. However, in patients with severe drug eruptions, anomalous overexpression of the formyl peptide receptor 1 (FPR1) in keratinocytes elicits a distinctive mode of cell death known as necroptosis, thereby suffering a loss of the skin barrier. The precise molecular mechanisms connecting FPR1 activation to this cell death remain unclear.

Objective: We have investigated the intracellular signal transduction cascade governing FPR1-mediated cell death in cultured keratinocytes.

Methods: We used HaCaT cells as a model keratinocyte. The expression of FPR1 was detected with qPCR. The presence of cell death events was monitored through live-cell fluorescent staining and LDH release assays. Furthermore, the phosphorylation of ERK was assessed via Western blot analysis. Intracellular signal pathways were investigated using specific inhibitors.

Results: Ligand stimulation of an endogenous ion channel, purinergic receptor P2X7 (P2X7R), increased the FPR1 expression level. This upregulated FPR1 demonstrated functional competence in the phosphorylation of downstream MAP kinase and the initiation of cell death. Notably, this cell death was ameliorated upon the administration of inhibitors targeting Gβγ, ERK, and caspases.

Conclusion: The induction and stimulation of FPR1 initiated apoptosis in keratinocytes via the Gβγ-pERK signaling pathway. Our findings postulate that the downstream components of FPR1 represent an alternative therapeutic target for preventing unintended keratinocyte cell death.

背景:细胞死亡是维持生物体内平衡的关键生物现象。在维持功能性皮肤屏障的过程中,角质形成细胞对细胞死亡信号进行正向和负向控制。然而,在严重药物疹患者中,角质形成细胞中甲酰肽受体 1(FPR1)的异常过度表达会引起一种称为坏死的独特细胞死亡模式,从而导致皮肤屏障的丧失。FPR1 激活与这种细胞死亡之间的确切分子机制仍不清楚:我们研究了细胞内调控 FPR1 介导的角质形成细胞死亡的信号转导级联:方法:我们使用 HaCaT 细胞作为模型角质形成细胞。方法:我们使用 HaCaT 细胞作为模型角质形成细胞,用 qPCR 检测 FPR1 的表达。通过活细胞荧光染色和 LDH 释放试验监测细胞死亡事件的存在。此外,还通过 Western 印迹分析评估了 ERK 的磷酸化情况。使用特异性抑制剂对细胞内信号通路进行了研究:结果:配体刺激内源性离子通道--嘌呤能受体 P2X7(P2X7R)可提高 FPR1 的表达水平。这种上调的 FPR1 在下游 MAP 激酶磷酸化和引发细胞死亡方面表现出功能性能力。值得注意的是,在使用针对 Gβγ、ERK 和 caspases 的抑制剂后,细胞死亡的情况得到了改善:结论:FPR1 的诱导和刺激可通过 Gβγ-pERK 信号通路引发角质形成细胞凋亡。我们的研究结果推测,FPR1 的下游成分是防止角质形成细胞意外死亡的另一个治疗靶点。
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引用次数: 0
Staphylococcus epidermidis augments human β-defensin-3 synthesis through the transforming growth factor alpha-epidermal growth factor receptor cascade 表皮葡萄球菌通过转化生长因子α-表皮生长因子受体级联促进人类β-防御素-3的合成
IF 4.6 Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.08.003
Rie Ommori, Satoru Shinkuma, Hideo Asada

Background

Epidermal growth factor receptor inhibitors (EGFRIs) reduce β-defensin 3 (BD3) from keratinocytes stimulated by S. epidermidis, potentially leading to the development of acneiform rashes in patients undergoing EGFRIs treatment. However, the mechanism through which S. epidermidis induces BD3 via EGFR remains incompletely understood.

Objective

To elucidate the BD3 production pathway triggered by S. epidermidis.

Methods

To assess the impact of S. epidermidis on EGFR ligand expression, the levels of released EGFR ligands in the keratinocyte culture medium following S. epidermidis stimulation were quantified using ELISA. Subsequently, to confirm the synergistic effect of TGF-α and S. epidermidis, we administered S. epidermidis and TGF-α to the keratinocyte culture medium and measured the expression levels of BD3. In addition, we stimulated Toll-like receptor 2 (TLR2)-knockdown keratinocytes with S. epidermidis and measured the expression levels of TGF-α.

Results

While S. epidermidis did not induce EGF and HB-EGF, they increased TGF-α. The expression of BD3 was higher in keratinocytes stimulated by S. epidermidis in the presence of TGF-α, as compared to its absence. Moreover, both S. epidermidis- and TGF-α-induced BD3 were significantly suppressed by cetuximab. The expression levels of TGF-α induced by S. epidermidis were reduced in TLR2-knockdown keratinocytes

Conclusion

Our findings suggest that S. epidermidis induces the expression of TGF-α in keratinocytes through TLR2, which, in cooperation with TGF-α, stimulates the production of BD3.
背景:表皮生长因子受体抑制剂(EGFRIs)可减少表皮葡萄球菌刺激角质形成细胞产生的β-防御素3(BD3),从而可能导致接受EGFRIs治疗的患者出现痤疮样皮疹。然而,表皮葡萄球菌通过表皮生长因子受体诱导 BD3 的机制仍不完全清楚:阐明表皮葡萄球菌诱导 BD3 的产生途径:为了评估表皮葡萄球菌对表皮生长因子受体配体表达的影响,使用 ELISA 定量表皮葡萄球菌刺激后角质形成细胞培养液中释放的表皮生长因子受体配体的水平。随后,为了证实 TGF-α 和表皮葡萄球菌的协同作用,我们在角质形成细胞培养液中加入了表皮葡萄球菌和 TGF-α,并测定了 BD3 的表达水平。此外,我们还用表皮葡萄球菌刺激了Toll样受体2(TLR2)敲除的角质形成细胞,并测量了TGF-α的表达水平:结果:表皮葡萄球菌没有诱导 EGF 和 HB-EGF,但增加了 TGF-α。在有 TGF-α 的情况下,表皮葡萄球菌刺激的角质形成细胞中 BD3 的表达量比没有 TGF-α 时要高。此外,西妥昔单抗还能显著抑制表皮葡萄球菌和 TGF-α 诱导的 BD3。表皮葡萄球菌诱导的 TGF-α 的表达水平在 TLR2-敲除的角质形成细胞中有所降低 结论:我们的研究结果表明,表皮葡萄球菌通过 TLR2 诱导角质形成细胞中 TGF-α 的表达,TLR2 与 TGF-α 合作刺激 BD3 的产生。
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引用次数: 0
Dermal fibroblasts retain site-specific transcriptomic identity in keloids 皮肤成纤维细胞在瘢痕疙瘩中保留了特定部位的转录组特征。
IF 4.6 Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.08.002
Pingping Lin , Daoning Zhang , Jie Tian , Binbin Lai , Yu Yang , Yicen Yan , Shenxi Zhang , Guohong Zhang , Hang Li

Background

Human skin displays extensive spatial heterogeneity and maintains distinct positional identity. However, the impact of disease processes on these site-specific differences remains poorly understood, especially in keloid, a skin disorder characterized by pronounced spatial heterogeneity.

Objective

This study aimed to assess whether the spatial heterogeneity and positional identity observed in different anatomic sites persist in keloids.

Methods

Transcriptome sequencing was conducted on 139 keloid dermal tissues and 19 keloid fibroblast samples spanning seven distinct anatomic sites to identify the spatial transcriptomic heterogeneity. In addition, single-cell RNA sequencing data were utilized to elucidate the contributions of various cell types to the maintenance of positional identity.

Results

Keloid dermal tissues from diverse sites were categorized into three anatomic groupings: trunk and extremity, ear, and mandible regions. Enrichment analysis of differentially expressed genes unveiled that keloids across distinct regions retained unique anatomically-related gene expression profiles, reminiscent of those observed in normal skin. Notably, regional disparities consistently prevailed and surpassed inter-donor variations. Single-cell RNA sequencing further revealed that mesenchymal cells, particularly fibroblasts, made major contributions to positional identity in keloids. Moreover, gene expression profiles in primary keloid fibroblasts demonstrated a remarkable persistence of positional identity, enduring even after prolonged in vitro propagation.

Conclusion

Taken together, these findings imply that keloids remain positional identity and developmental imprinting characteristic of normal skin. Fibroblasts predominantly contribute to the spatial heterogeneity observed in keloids.
背景:人类皮肤具有广泛的空间异质性,并保持着独特的位置特性。然而,人们对疾病过程对这些特定部位差异的影响仍然知之甚少,尤其是对瘢痕疙瘩这种以明显的空间异质性为特征的皮肤疾病:本研究旨在评估在不同解剖部位观察到的空间异质性和位置同一性在瘢痕疙瘩中是否持续存在:方法:对139个瘢痕疙瘩真皮组织和19个瘢痕疙瘩成纤维细胞样本进行转录组测序,横跨7个不同的解剖部位,以确定空间转录组异质性。此外,还利用单细胞 RNA 测序数据来阐明各种细胞类型对位置特性维持的贡献:结果:来自不同部位的瘢痕疙瘩真皮组织被分为三个解剖组:躯干和四肢、耳朵和下颌区域。差异表达基因的富集分析表明,不同区域的瘢痕疙瘩保留了独特的解剖相关基因表达谱,与正常皮肤中观察到的基因表达谱相似。值得注意的是,区域差异始终占主导地位,并超过了供体间差异。单细胞 RNA 测序进一步显示,间充质细胞,尤其是成纤维细胞,对瘢痕疙瘩的位置特征做出了重要贡献。此外,原发性瘢痕疙瘩成纤维细胞的基因表达图谱显示,位置特征具有显著的持久性,即使在体外长期繁殖后仍能保持:综上所述,这些研究结果表明,瘢痕疙瘩仍具有正常皮肤的位置特征和发育印记。成纤维细胞是瘢痕疙瘩空间异质性的主要成因。
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引用次数: 0
Dysbiosis-activated IL-17-producing T cells promote skin immunopathological progression in mice deficient of the Notch ligand Jag1 in keratinocytes 在角质形成细胞中缺乏 Notch 配体 Jag1 的小鼠体内,菌群失调激活的产生 IL-17 的 T 细胞会促进皮肤免疫病理学的发展。
IF 4.6 Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.09.001
Eun Hyeon Song , Juan Garcia Jr. , Na Xiong

Background

The Notch signaling pathway is an evolutionarily conserved regulatory cascade critical in skin development and homeostasis. Mice deficient of Notch signaling molecules have impaired skin and hair follicle development associated with local tissue inflammation. However, mechanisms underlying skin inflammation and pathology resulting from defective Notch signals are not well understood.

Objective

To dissect molecular and cellular mechanisms underlying development of skin immunopathology in mice defective of the Notch ligand Jagged-1 (Jag1).

Methods

We assessed involvement of microbiota and immune cell subsets in skin pathogenic symptoms in Foxn1CreJag1fl/fl mice that were deficient of Jag1 in keratinocytes. We also used RNA-seq and 16S rRNA gene-seq analyses to identify molecular factors and bacterial species contributing to skin pathologic symptoms in Foxn1CreJag1fl/fl mice.

Results

Compared to Jag1-sufficient littermate control mice, Foxn1CreJag1fl/fl mice had specific expansion of IL-17a-producing T cells accompanying follicular and epidermal hyperkeratosis and cyst formation while antibody blockage of IL-17a reduced the skin pathology. RNA-sequencing and 16S rRNA gene-sequencing analyses revealed dysregulated immune responses and altered microbiota compositions in the skin of Foxn1CreJag1fl/fl mice. Antibiotic treatment completely prevented over-activation of IL-17a-producing T cells and alleviated skin pathology in Foxn1CreJag1fl/fl mice.

Conclusion

Dysbiosis-induced over-activation of IL-17a-producing T cells is critically involved in development of skin pathology in Foxn1CreJag1fl/fl mice, establishing Foxn1CreJag1fl/fl mice as a useful model to study pathogenesis and therapeutic targets in microbiota-IL-17-mediated skin inflammatory diseases such as hidradenitis suppurativa (HS) and psoriasis.
背景:Notch 信号通路是一种进化保守的调控级联,对皮肤发育和稳态至关重要。缺乏 Notch 信号分子的小鼠皮肤和毛囊发育受损,并伴有局部组织炎症。然而,Notch 信号缺陷导致的皮肤炎症和病理机制尚不十分清楚:目的:研究 Notch 配体 Jagged-1 (Jag1) 缺陷小鼠皮肤免疫病理学发展的分子和细胞机制:我们评估了Foxn1CreJag1fl/fl小鼠皮肤致病症状中微生物群和免疫细胞亚群的参与情况,这些小鼠的角质形成细胞中缺乏Jag1。我们还利用RNA-seq和16S rRNA基因-seq分析确定了导致Foxn1CreJag1fl/fl小鼠皮肤病理症状的分子因素和细菌种类:结果:与Jag1不足的同窝对照小鼠相比,Foxn1CreJag1fl/fl小鼠产生IL-17a的T细胞特异性扩增,并伴有滤泡和表皮角化过度和囊肿形成,而抗体阻断IL-17a可减轻皮肤病理变化。RNA 序列和 16S rRNA 基因序列分析表明,Foxn1CreJag1fl/fl 小鼠皮肤的免疫反应失调,微生物群组成发生改变。抗生素治疗可完全阻止产生 IL-17a 的 T 细胞过度激活,并减轻 Foxn1CreJag1fl/fl 小鼠的皮肤病理变化:Foxn1CreJag1fl/fl小鼠皮肤病理学的发展关键在于菌群失调诱导的产生IL-17a的T细胞过度激活,因此Foxn1CreJag1fl/fl小鼠是研究微生物-IL-17介导的皮肤炎症性疾病(如化脓性扁桃体炎(HS)和银屑病)的发病机制和治疗靶点的有用模型。
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引用次数: 0
Possible facilitating role of IL-17A on IL-23 production in keratinocytes in psoriatic lesions IL-17A 可能对银屑病皮损中角质细胞产生 IL-23 起到促进作用。
IF 4.6 Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.09.002
Akimasa Adachi , Tetsuya Honda , Nobuhiro Kusuba , Fuuka Minami , Satoshi Nakamizo , Kenji Kabashima
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引用次数: 0
期刊
Journal of dermatological science
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