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IF 4.6

Journal of dermatological science

Pub Date : 2025-01-01 DOI: 10.1016/S0923-1811(25)00007-6

引用次数: 0

Improvement of immunological tests for detecting autoantibodies in patients with lamina lucida-type linear IgA bullous dermatosis 改进免疫学试验，以检测透明层型线性 IgA 大疱性皮肤病患者的自身抗体。

IF 4.6

Journal of dermatological science

Pub Date : 2025-01-01 DOI: 10.1016/j.jdermsci.2024.12.001

Masahiro Tsutsumi , Hiroshi Koga , Kwesi Teye , Norito Ishii , Takekuni Nakama

Background

In the diagnosis of linear IgA bullous dermatosis (LABD), detection of IgA at the epidermal basement membrane zone and circulating IgA autoantibodies are essential. The disease has two subtypes, lamina lucida-type and sublamina densa-type, with 120 kDa LAD-1 and 97 kDa LABD97 as major autoantigens for lamina lucida-type. Normal human epidermal keratinocytes (NHEK) and HaCaT cells are widely used for immunoblotting (IB) in the diagnosis process, but they do not provide high sensitivity and semiquantitative analysis.

Objective

To develop a more sensitive and convenient method for detecting IgA antibodies in lamina lucida-type LABD patients.

Methods

The expressions of LAD-1 and LABD97 in lysates and culture supernatants from Ker-CT, HaCaT, DJM-1, and NHEK were compared. The sensitivity of IBs using concentrated culture supernatants of HaCaT and Ker-CT and ELISAs using several recombinant proteins (RPs) corresponding to BP180 ectodomain were compared using 55 sera from LABD patients.

Results

In culture supernatant, Ker-CT expressed higher amounts of LAD-1 and LABD97. IBs using concentrated culture supernatant of HaCaT and Ker-CT showed 43 % and 46 % positivity to sera from LABD patients, respectively. In ELISAs, the RP of amino acids 490–1421 of BP180 showed the highest positivity (80.0 %) among several proteins. Additionally, this ELISA showed reduced OD values in LABD and related diseases patients' sera at remission.

Conclusion

The ELISA using the RP coding amino acids 490–1421 of BP180 is useful for identifying IgA antibodies and monitoring disease activity in lamina lucida-type LABD patients.

背景：在线性IgA大疱性皮肤病（LABD）的诊断中，检测表皮基底膜区IgA和循环IgA自身抗体是必不可少的。该疾病有两种亚型，即透明层型和膜下致密型，其中120 kDa LAD-1和97 kDa LABD97是透明层型的主要自身抗原。正常人表皮角质形成细胞（NHEK）和HaCaT细胞在诊断过程中广泛用于免疫印迹（IB），但它们不能提供高灵敏度和半定量分析。目的：建立一种更灵敏、简便的检测透明层型LABD患者IgA抗体的方法。方法：比较Ker-CT、HaCaT、DJM-1和NHEK的裂解液和培养上清液中LAD-1和LABD97的表达。用55例LABD患者的血清比较HaCaT和Ker-CT的浓培养上清和BP180外结构域对应的重组蛋白（RPs）的elisa的敏感性。结果：培养上清中，Ker-CT表达较高的lad1和LABD97。使用HaCaT和Ker-CT浓缩培养上清的IBs对LABD患者血清的阳性率分别为43% %和46% %。在酶联免疫吸附试验中，BP180的490 ~ 1421氨基酸的RP在几种蛋白中阳性率最高（80.0 %）。此外，该ELISA显示，缓解期LABD及相关疾病患者血清中的OD值降低。结论：利用RP编码BP180蛋白490 ~ 1421氨基酸的酶联免疫吸附试验（ELISA）可用于荧光层型LABD患者的IgA抗体鉴定和疾病活动性监测。

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引用次数: 0

Upregulation of TLR2 in keratinocytes activates the MAPK pathway and plays a role in the pathogenesis of hidradenitis suppurativa 角化细胞中TLR2的上调激活了MAPK通路，并在化脓性汗腺炎的发病机制中发挥作用。

IF 4.6

Journal of dermatological science

Pub Date : 2025-01-01 DOI: 10.1016/j.jdermsci.2024.11.002

Haini Zhang, Yi Li, Xiaodong Lai, Chong Zhang, Zhongshuai Wang, Yan Yang, Baoxi Wang , Yan Yan

Background

Mutations in gamma-secretase complex (GSC) genes are associated with hidradenitis suppurativa (HS), and toll-like receptor (TLR) 2 is elevated in HS lesions. However, it remains unclear whether TLR2 is upregulated in the skin lesions of patients with HS with GSC gene variants, and the role of its upregulation in the pathogenesis of this disease are unknown.

Objective

To investigate the role of TLR2 upregulation in NCSTN and PSENEN knockdown keratinocytes.

Methods

Human immortalized keratinocyte line (HaCaTs) was treated with potent short-hairpin RNA targeting NCSTN or PSENEN. RNA sequencing was used to assess the effects of PAM2CSK4 treatment on gene expression in HaCaT cells. Altered signaling pathways were confirmed in both HaCaT cells, as well as in skin lesions from patients with HS and in Ncstn keratinocyte-specific knockout (Ncstn^ΔKC) mice.

Results

TLR2 agonist stimulation exacerbated the increased phosphorylation levels of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) in NCSTN- and PSENEN- knockdown keratinocytes. Similar findings were observed in skin lesions from patients with HS and Ncstn^ΔKC mice.

Conclusion

Novel variations were identified within the GSC gene in Chinese patients with HS. Moreover, our study indicates that TLR2/MAPK signaling pathways play a key role in the pathogenesis of HS associated with GSC gene mutations and represent a crucial therapeutic target.

背景：γ -分泌酶复合物（GSC）基因突变与化脓性汗腺炎（HS）有关，而toll样受体（TLR） 2在HS病变中升高。然而，目前尚不清楚TLR2在GSC基因变异的HS患者皮损中是否上调，其上调在该疾病发病机制中的作用尚不清楚。目的：探讨TLR2上调在NCSTN和PSENEN敲低角质形成细胞中的作用。方法：用靶向NCSTN或PSENEN的强效短发夹RNA处理人永生化角化细胞系（HaCaTs）。采用RNA测序法评估PAM2CSK4处理对HaCaT细胞基因表达的影响。在HaCaT细胞、HS患者皮肤病变和Ncstn角化细胞特异性敲除（NcstnΔKC）小鼠中均证实了信号通路的改变。结果：TLR2激动剂刺激加剧了NCSTN-和PSENEN-敲低角质形成细胞中细胞外信号调节激酶1/2和p38丝裂原活化蛋白激酶（MAPK）磷酸化水平的升高。在HS患者和NcstnΔKC小鼠的皮肤病变中也观察到类似的结果。结论：在中国HS患者中发现了新的GSC基因变异。此外，我们的研究表明，TLR2/MAPK信号通路在与GSC基因突变相关的HS发病机制中起关键作用，是一个重要的治疗靶点。

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引用次数: 0

Cytosolic mtDNA-cGAS-STING axis mediates melanocytes pyroptosis to promote CD8⁺ T-cell activation in vitiligo. 细胞质mtDNA-cGAS-STING轴介导黑色素细胞热解，促进白癜风患者CD8+T细胞的活化。

IF 4.6

Journal of dermatological science

Pub Date : 2024-12-26 DOI: 10.1016/j.jdermsci.2024.12.002

Xinya Xu, Xinhua Lu, Yue Zheng, Yang Xie, Wei Lai

Background: The cGAS-STING axis, a DNA sensor pathway, has recently emerged as a key hub in sensing stress signals and initiating the immune cascade in several diseases. However, its role in the pathogenesis of vitiligo remains unclear.

Objective: To explore the pathogenic role of the cGAS-STING axis in linking oxidative stress and CD8⁺ T-cell-mediated anti-melanocytic immunity in vitiligo.

Methods: The expression status of the cGAS-STING axis and cytosolic mtDNA were evaluated in the oxidatively stressed epidermal cells and vitiligo perilesional skin, respectively. Then, we investigated the activation of cGAS-STING axis in mtDNA-treated melanocytes, and the influence of cGAS or STING silencing on mtDNA-induced melanocytes pyroptosis. Finally, the paracrine effects of melanocytes pyroptosis on CD8⁺ T cell activation were explored.

Results: We initially demonstrated that the cGAS-STING axis in melanocytes was highly susceptible to oxidative stress and activated in the vitiliginous melanocytes of perilesional skin, accompanied by enhanced cytosolic mtDNA accumulation. Our mechanistic in vitro experiments confirmed that oxidative stress-induced mitochondrial damage in epidermal cells led to cytosolic mtDNA accumulation, which served as a trigger in activating the cGAS-STING axis in melanocytes. Furthermore, the cytosolic mtDNA-cGAS-STING axis was verified to mediate melanocytes pyroptosis. More importantly, we found that IL-1β and IL-18 produced by pyroptotic melanocytes promoted the activation of CD8⁺ T cells from patients with vitiligo.

Conclusion: The present study confirmed that the cytosolic mtDNA-cGAS-STING axis of melanocytes played an important role in oxidative stress-triggered CD8⁺ T-cell response, providing novel insights into mechanisms underlying vitiligo onset.

背景：cGAS-STING轴是一种DNA传感器通路，最近已成为在多种疾病中感知应激信号和启动免疫级联的关键枢纽。然而，它在白癜风发病机制中的作用仍不清楚：探讨cGAS-STING轴在白癜风患者氧化应激和CD8+ T细胞介导的抗黑色素细胞免疫中的致病作用：方法：分别评估了氧化应激表皮细胞和白癜风周围皮肤中cGAS-STING轴和细胞膜mtDNA的表达状况。然后，我们研究了经mtDNA处理的黑色素细胞中cGAS-STING轴的激活情况，以及cGAS或STING沉默对mtDNA诱导的黑色素细胞脓毒症的影响。最后，我们还探讨了黑色素细胞热凋亡对 CD8+ T 细胞活化的旁分泌效应：我们初步证明了黑色素细胞中的 cGAS-STING 轴极易受到氧化应激的影响，并在绒毛周围皮肤的白癜风黑色素细胞中被激活，同时伴随着细胞膜 mtDNA 积累的增强。我们的体外机理实验证实，氧化应激诱导的表皮细胞线粒体损伤会导致细胞膜mtDNA积累，而mtDNA积累是激活黑色素细胞cGAS-STING轴的触发器。此外，我们还验证了细胞膜 mtDNA-cGAS-STING 轴介导了黑色素细胞的脓毒症。更重要的是，我们发现嗜热黑色素细胞产生的IL-1β和IL-18能促进白癜风患者CD8+T细胞的活化：本研究证实，黑色素细胞的细胞质mtDNA-cGAS-STING轴在氧化应激触发的CD8+ T细胞反应中发挥了重要作用，为了解白癜风的发病机制提供了新的视角。

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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

Journal of dermatological science

Pub Date : 2024-12-01 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

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

Journal of dermatological science

Pub Date : 2024-12-01 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+ 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":"10.1016/j.jdermsci.2024.10.003","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Objectives</h3><div>To examine the expression of NLRP3 inflammasome and their skin migration in CBZE-induced SJS/TEN.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"116 3","pages":"Pages 80-89"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","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

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

Journal of dermatological science

Pub Date : 2024-12-01 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。

{"title":"Genome-wide DNA methylation regulated by AHCY through SAM / SAH axis promotes psoriasis pathogenesis","authors":"Lingxi Liu , Lihao Chen , Yu Hu , Qian Zhang , Kun Chen , Jiaan Zhang","doi":"10.1016/j.jdermsci.2024.10.004","DOIUrl":"10.1016/j.jdermsci.2024.10.004","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Objective</h3><div>This study aimed to investigate the role of AHCY and its impact on DNA methylation in psoriasis pathogenesis.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":94076,"journal":{"name":"Journal of dermatological science","volume":"116 3","pages":"Pages 100-110"},"PeriodicalIF":4.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635161","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

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

Journal of dermatological science

Pub Date : 2024-12-01 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

Editors Choice

IF 4.6

Journal of dermatological science

Pub Date : 2024-12-01 DOI: 10.1016/S0923-1811(24)00229-9

引用次数: 0

Unveiling intratumoral heterogeneity in high-risk cutaneous squamous cell carcinoma using single-cell spatial enhanced resolution omics-sequencing (Stereo-seq). 利用单细胞空间增强分辨率组学测序（Stereo-seq）揭示高风险皮肤鳞状细胞癌的肿瘤内异质性。

IF 4.6

Journal of dermatological science

Pub Date : 2024-11-16 DOI: 10.1016/j.jdermsci.2024.11.001

Jesse Veenstra, Ian Loveless, Peter Dimitrion, Indra Adrianto, David Ozog, Qing-Sheng Mi

引用次数: 0