Journal of dermatological science最新文献

英文中文

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 : 2024-10-06 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

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.08.003

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

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.08.002

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

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.09.001

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 Foxn1^CreJag1^fl/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 Foxn1^CreJag1^fl/fl mice.

Results

Compared to Jag1-sufficient littermate control mice, Foxn1^CreJag1^fl/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 Foxn1^CreJag1^fl/fl mice. Antibiotic treatment completely prevented over-activation of IL-17a-producing T cells and alleviated skin pathology in Foxn1^CreJag1^fl/fl mice.

Conclusion

Dysbiosis-induced over-activation of IL-17a-producing T cells is critically involved in development of skin pathology in Foxn1^CreJag1^fl/fl mice, establishing Foxn1^CreJag1^fl/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

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.09.002

引用次数: 0

Serum inflammatory biomarkers associated with disease severity and response to dupilumab treatment in bullous pemphigoid: A cluster analysis 与大疱性类天疱疮疾病严重程度和对杜匹单抗治疗反应相关的血清炎症生物标志物：聚类分析

IF 4.6

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.09.003

Background

Dupilumab, a novel therapy targeting the T helper (Th) 2-mediated inflammation, is showing clinical benefits in treating bullous pemphigoid (BP). However, limited research investigated the serum biomarkers that reflect the inflammation alterations throughout the disease course.

Objectives

To explore the changes of the serum inflammatory biomarkers under dupilumab therapy in BP and establish their correlations with disease severity and clinical outcomes.

Methods

This exploratory study evaluated serum samples from 40 patients with BP at baseline, 30 of these patients following 16-week dupilumab therapy, and 20 senior healthy controls. Serum levels of 29 cytokines and chemokines were quantified using the Magnetic Luminex Assay.

Results

Two distinct clusters based on serum inflammatory profiles were identified. The first cluster, characterized by elevated levels of inflammatory activation, exhibited worse disease severity and poorer remission outcomes. Following the 16-week dupilumab therapy regimen, a significant suppression of Th2-mediated inflammation in the serum was observed, alongside a relative upregulation of Th1 responses. Patients treated with adjuvant systemic steroids exhibited an enhanced suppression of B cell activating factor compared to those receiving dupilumab alone. Significant correlations were unveiled between Th2 biomarkers and clinical scores, eosinophil counts, and anti-BP180 immunoglobulin G levels. Baseline levels of CCL18, Periostin, interleukin (IL)-6, and IL-16 constitute an optimal combination to distinguish between inflammatory clusters.

Conclusions

Cluster analysis of serum inflammatory biomarkers provided novel insights into the heterogeneity of the inflammation profiles in BP. Baseline levels of CCL18, Periostin, IL-6, IL-16 emerged as effective predictors for disease severity and therapy response to dupilumab.

背景：Dupilumab是一种针对T辅助细胞（Th）2介导的炎症的新型疗法，在治疗大疱性类天疱疮（BP）方面显示出临床疗效。然而，对反映整个病程中炎症变化的血清生物标志物的研究却很有限：目的：探讨杜匹单抗治疗大疱性类天疱疮时血清炎症生物标志物的变化，并确定其与疾病严重程度和临床结果的相关性：这项探索性研究评估了 40 名 BP 患者基线时的血清样本、其中 30 名患者接受 16 周杜匹单抗治疗后的血清样本以及 20 名资深健康对照者的血清样本。使用 Magnetic Luminex Assay 对 29 种细胞因子和趋化因子的血清水平进行了量化：结果：根据血清炎症特征确定了两个不同的群组。第一组的特点是炎症激活水平升高，疾病严重程度更严重，缓解效果更差。在接受为期16周的dupilumab治疗后，观察到血清中Th2介导的炎症明显抑制，同时Th1反应相对上调。与单独接受杜比单抗治疗的患者相比，接受辅助性全身类固醇治疗的患者表现出更强的B细胞活化因子抑制能力。Th2生物标记物与临床评分、嗜酸性粒细胞计数和抗BP180免疫球蛋白G水平之间存在显著相关性。CCL18、Periostin、白细胞介素（IL）-6和IL-16的基线水平是区分炎症集群的最佳组合：血清炎症生物标志物的聚类分析为了解血压炎症特征的异质性提供了新的视角。CCL18、Periostin、IL-6、IL-16的基线水平可有效预测疾病的严重程度和对dupilumab的治疗反应。

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引用次数: 0

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IF 4.6

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/S0923-1811(24)00207-X

引用次数: 0

Recombinant human thioredoxin ameliorates imiquimod-induced psoriasis-like dermatitis in mice 重组人硫氧还蛋白可改善咪喹莫特诱导的小鼠银屑病样皮炎。

IF 4.6

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.07.002

引用次数: 0

Ferrostatin-1 alleviates skin inflammation and inhibits ferroptosis of neutrophils and CD8+ T cells in allergic contact dermatitis 铁前列素-1 可减轻过敏性接触性皮炎的皮肤炎症反应，并抑制中性粒细胞和 CD8+ T 细胞的铁凋亡。

IF 4.6

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/j.jdermsci.2024.08.004

Background

Ferroptosis is considered as an immunogenic type of regulated cell death and associated with the pathogenesis of inflammatory skin diseases. However, the involvement and function of ferroptosis in allergic contact dermatitis (ACD) remains unknown.

Objective

To explore the role of ferroptosis in ACD. To reveal which type of cells develops ferroptosis in ACD.

Methods

We detected the key markers of ferroptosis in 1-Chloro-2,4-dinitrochlorobenzene (DNCB)-induced ACD mice model. We applicated ferrostatin-1 (Fer-1) to restrain ferroptosis in ACD mice and then compared the severity of dermatitis and the level of inflammation and ferroptosis in dermis and epidermis, respectively. Keratinocyte-specific Gpx4 conditional knockout (cKO) mice were used to investigate the function of keratinocyte ferroptosis in the development of ACD. Single-cell RNA sequencing was conducted to analyze the affection of Fer-1 on different type of cells in ACD.

Results

Ferroptosis was involved in DNCB-induced ACD mice. Ferroptosis activation was more remarkable in dermis rather than in epidermis. Gpx4 cKO mice showed similar severity of skin dermatitis as control mice. Fer-1 alleviated skin inflammation in mice and reduced ferroptosis in neutrophils and CD8⁺ T cells both of which contribute to development of ACD.

Conclusion

Ferroptosis was activated in immune cells, especially neutrophils and CD8⁺ T cells in DNCB-induced ACD mice. Fer-1 treatment inhibited ferroptosis of neutrophils and CD8⁺ T cells and relieved skin damage in ACD mice.

背景：铁蛋白沉积被认为是一种调节细胞死亡的免疫原性类型，与炎症性皮肤病的发病机制有关。然而，过敏性接触性皮炎（ACD）中铁细胞凋亡的参与和功能仍不清楚：目的：探讨嗜铁细胞增多症在过敏性接触性皮炎中的作用。揭示在 ACD 中哪种类型的细胞会发生铁蛋白沉积：方法：我们在 1-氯-2,4-二硝基氯苯（DNCB）诱导的 ACD 小鼠模型中检测了铁变态反应的关键标志物。我们使用铁前列素-1（Fer-1）抑制ACD小鼠的铁蛋白沉积，然后比较皮炎的严重程度以及真皮和表皮的炎症和铁蛋白沉积水平。用角质细胞特异性Gpx4条件性基因敲除（cKO）小鼠来研究角质细胞铁突变在ACD发病中的功能。通过单细胞RNA测序分析了Fer-1对ACD中不同类型细胞的影响：结果：铁突变参与了 DNCB 诱导的 ACD 小鼠。结果：铁凋亡参与了 DNCB 诱导的 ACD 小鼠，铁凋亡激活在真皮层比在表皮层更显著。Gpx4 cKO 小鼠皮肤皮炎的严重程度与对照组小鼠相似。Fer-1减轻了小鼠的皮肤炎症，减少了中性粒细胞和CD8+ T细胞中的铁突变，而这两种细胞都会导致ACD的发生：结论：在 DNCB 诱导的 ACD 小鼠中，免疫细胞，尤其是中性粒细胞和 CD8+ T 细胞中的铁蛋白沉积被激活。Fer-1 治疗可抑制中性粒细胞和 CD8+ T 细胞的铁突变，缓解 ACD 小鼠的皮肤损伤。

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引用次数: 0

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IF 4.6

Journal of dermatological science

Pub Date : 2024-10-01 DOI: 10.1016/S0923-1811(24)00204-4

引用次数: 0

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