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Comparative Analysis of Extracellular Vesicles from Cytotoxic CD8+ αβ T Cells and γδ T Cells. 细胞毒性 CD8+ αβ T 细胞和 γδ T 细胞胞外囊泡的比较分析
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-21 DOI: 10.3390/cells13201745
Lisa Griesel, Patrick Kaleja, Andreas Tholey, Marcus Lettau, Ottmar Janssen

Background: Although belonging to different branches of the immune system, cytotoxic CD8+ αβ T cells and γδ T cells utilize common cytolytic effectors including FasL, granzymes, perforin and granulysin. The effector proteins are stored in different subsets of lysosome-related effector vesicles (LREVs) and released to the immunological synapse upon target cell encounter. Notably, in activated cells, LREVs and potentially other vesicles are continuously produced and released as extracellular vesicles (EVs). Presumably, EVs serve as mediators of intercellular communication in the local microenvironment or at distant sites.

Methods: EVs of activated and expanded cytotoxic CD8+ αβ T cells or γδ T cells were enriched from culture supernatants by differential and ultracentrifugation and characterized by nanoparticle tracking analyses and Western blotting. For a comparative proteomic profiling, EV preparations from both cell types were isobaric labeled with tandem mass tags (TMT10plex) and subjected to mass spectrometry analysis.

Results: 686 proteins were quantified in EV preparations of cytotoxic CD8+ αβ T cells and γδ T cells. Both populations shared a major set of similarly abundant proteins, while much fewer proteins presented higher abundance levels in either CD8+ αβ T cells or γδ T cells. To our knowledge, we provide the first comparative analysis of EVs from cytotoxic CD8+ αβ T cells and γδ T cells.

背景:细胞毒性 CD8+αβ T 细胞和 γδ T 细胞虽然属于免疫系统的不同分支,但它们利用共同的细胞溶解效应物,包括 FasL、颗粒酶、穿孔素和颗粒溶素。效应蛋白储存在溶酶体相关效应囊(LREVs)的不同亚群中,遇到靶细胞时释放到免疫突触。值得注意的是,在活化细胞中,溶酶体相关效应囊泡和其他可能的囊泡不断产生并以细胞外囊泡(EVs)的形式释放出来。据推测,EVs 可作为本地微环境或远处细胞间通信的媒介:方法:用差速和超速离心法从培养上清液中富集活化和扩增的细胞毒性 CD8+ αβ T 细胞或 γδ T 细胞的 EVs,并用纳米颗粒追踪分析和 Western 印迹法对其进行表征。为了进行比较蛋白质组学分析,对来自两种细胞类型的EV制备物进行了串联质量标签(TMT10plex)等位标记,并进行了质谱分析:结果:在细胞毒性 CD8+ αβ T 细胞和 γδ T 细胞的 EV 制剂中定量检测了 686 种蛋白质。这两种细胞群共享一组主要的相似丰度蛋白,而在 CD8+ αβ T 细胞或 γδ T 细胞中出现较高丰度水平的蛋白要少得多。据我们所知,我们首次对来自细胞毒性 CD8+ αβ T 细胞和 γδ T 细胞的 EVs 进行了比较分析。
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引用次数: 0
Correction: Szymanska et al. The Effect of Visfatin on the Functioning of the Porcine Pituitary Gland: An In Vitro Study. Cells 2023, 12, 2835. 更正:Szymanska et al.《Visfatin 对猪垂体功能的影响》:体外研究。细胞 2023,12,2835。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-21 DOI: 10.3390/cells13201741
Karolina Szymanska, Edyta Rytelewska, Ewa Zaobidna, Marta Kiezun, Marlena Gudelska, Grzegorz Kopij, Kamil Dobrzyn, Ewa Mlyczynska, Patrycja Kurowska, Barbara Kaminska, Anna Nynca, Nina Smolinska, Agnieszka Rak, Tadeusz Kaminski

In the original publication [...].

在最初的出版物中 [......] 。
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引用次数: 0
N6-Methyladenosine RNA Modification Regulates the Differential Muscle Development in Large White and Ningxiang Pigs. N6-甲基腺苷RNA修饰调控大白猪和宁乡猪的肌肉发育差异
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-21 DOI: 10.3390/cells13201744
Hao Gu, Kang Xu, Zhao Yu, Zufeng Ren, Fan Chen, Changfan Zhou, Wei Zeng, Hongyan Ren, Yulong Yin, Yanzhen Bi

N6-methyladenosine (m6A) is the most common modification in eukaryotic RNAs. Growing research indicates that m6A methylation is crucial for a multitude of biological processes. However, research on the m6A modifications in the regulation of porcine muscle growth is lacking. In this study, we identified differentially expressed genes in the neonatal period of muscle development between Large White (LW) and NingXiang (NX) pigs and further reported m6A methylation patterns via MeRIP-seq. We found that m6A modification regulates muscle cell development, myofibrils, cell cycle, and phosphatase regulator activity during the neonatal phase of muscle development. Interestingly, differentially expressed genes in LW and NX pigs were mainly enriched in pathways involved in protein synthesis. Furthermore, we performed a conjoint analysis of MeRIP-seq and RNA-seq data and identified 27 differentially expressed and m6A-modified genes. Notably, a typical muscle-specific envelope transmembrane protein, WFS1, was differentially regulated by m6A modifications in LW and NX pigs. We further revealed that the m6A modification accelerated the degradation of WFS1 in a YTHDF2-dependent manner. Noteworthy, we identified a single nucleotide polymorphism (C21551T) within the last exon of WFS1 that resulted in variable m6A methylation, contributing to the differing WFS1 expression levels observed in LW and NX pigs. Our study conducted a comprehensive analysis of the m6A modification on NX and LW pigs during the neonatal period of muscle development, and elucidated the mechanism by which m6A regulates the differential expression of WFS1 in the two breeds.

N6-甲基腺苷(m6A)是真核 RNA 中最常见的修饰。越来越多的研究表明,m6A 甲基化对多种生物过程至关重要。然而,有关 m6A 修饰在猪肌肉生长调控中的作用的研究还很缺乏。在这项研究中,我们鉴定了大白猪(LW)和宁乡猪(NX)新生儿期肌肉发育过程中的差异表达基因,并通过 MeRIP-seq 进一步报告了 m6A 甲基化模式。我们发现,在肌肉发育的新生阶段,m6A修饰调控着肌肉细胞发育、肌原纤维、细胞周期和磷酸酶调控因子的活性。有趣的是,LW 猪和 NX 猪的差异表达基因主要富集在参与蛋白质合成的通路中。此外,我们还对 MeRIP-seq 和 RNA-seq 数据进行了联合分析,发现了 27 个差异表达基因和 m6A 修饰基因。值得注意的是,一种典型的肌肉特异性包膜跨膜蛋白 WFS1 在 LW 猪和 NX 猪中受到 m6A 修饰的不同调控。我们进一步发现,m6A修饰以一种依赖于YTHDF2的方式加速了WFS1的降解。值得注意的是,我们在 WFS1 的最后一个外显子中发现了一个单核苷酸多态性(C21551T),该多态性导致了不同的 m6A 甲基化,从而导致了在 LW 猪和 NX 猪中观察到的不同的 WFS1 表达水平。我们的研究对 NX 猪和 LW 猪新生儿期肌肉发育过程中的 m6A 修饰进行了全面分析,并阐明了 m6A 调节两个品种 WFS1 不同表达的机制。
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引用次数: 0
Asparagine614 Determines the Transport and Function of the Murine Anti-Aging Protein Klotho. 天冬酰胺 614 决定小鼠抗衰老蛋白 Klotho 的运输和功能
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-21 DOI: 10.3390/cells13201743
Zahra Fanaei-Kahrani, Christoph Kaether

Klotho is an anti-aging protein whose deletion significantly reduces lifespan in mice, while its over-expression increases lifespan. Klotho is a type-I transmembrane protein that is N-glycosylated at eight positions within its ectodomain. Our study demonstrates that N-glycosylation or mutation at position N614, but not at N161, N285, or N346 in mouse Klotho, is critically involved in the transport of Klotho out of the endoplasmic reticulum (ER). Consequently, while wild-type Klotho-EGFP as well as the N-glycosylation mutants N161Q, N285Q, and N346Q were present at the plasma membrane (PM), only small amounts of the N614Q Klotho-EGFP were present at the PM, with most of the protein accumulating in the ER. Protein interactome analysis of Klotho-EGFP N614Q revealed increased interactions with proteasome-related proteins and proteins involved in ER protein processing, like heat shock proteins and protein disulfide isomerases, indicative of impaired protein folding. Co-immunoprecipitation experiments confirmed the interaction of Klotho-EGFP N614Q with ER chaperons. Interestingly, despite the low amounts of Klotho-EGFP N614Q at the PM, it efficiently induced FGF receptor-mediated ERK activation in the presence of FGF23, highlighting its efficacy in triggering downstream signaling, even in limited quantities at the PM.

Klotho 是一种抗衰老蛋白,其缺失会显著缩短小鼠的寿命,而过度表达则会延长寿命。Klotho 是一种 I 型跨膜蛋白,在其外显子结构域的八个位置有 N-糖基化。我们的研究表明,在小鼠 Klotho 中,N614 位(而不是 N161、N285 或 N346 位)的 N-糖基化或突变是 Klotho 从内质网(ER)转运出去的关键。因此,野生型 Klotho-EGFP 以及 N-糖基化突变体 N161Q、N285Q 和 N346Q 存在于质膜(PM),而 N614Q Klotho-EGFP 仅有少量存在于质膜,大部分蛋白质积聚在 ER 中。Klotho-EGFP N614Q 的蛋白质相互作用组分析表明,它与蛋白酶体相关蛋白质和参与ER蛋白质加工的蛋白质(如热休克蛋白和蛋白质二硫异构酶)的相互作用增加,表明蛋白质折叠受损。共免疫沉淀实验证实了 Klotho-EGFP N614Q 与 ER伴侣的相互作用。有趣的是,尽管 Klotho-EGFP N614Q 在 PM 中的含量很低,但在 FGF23 的存在下,它能有效地诱导 FGF 受体介导的 ERK 激活,这凸显了它在触发下游信号转导方面的功效,即使在 PM 中的含量有限。
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引用次数: 0
DNA-Binding Protein A Is Actively Secreted in a Calcium-and Inflammasome-Dependent Manner and Negatively Influences Tubular Cell Survival. DNA 结合蛋白 A 以钙和炎症依赖的方式主动分泌,并对肾小管细胞的存活产生负面影响。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-21 DOI: 10.3390/cells13201742
Gregor Hoppstock, Jonathan A Lindquist, Antonia Willems, Annika Becker, Charlotte Reichardt, Ronnie Morgenroth, Saskia Stolze, Cheng Zhu, Sabine Brandt, Peter R Mertens

DNA-binding protein A (DbpA) belongs to the Y-box family of cold shock domain (CSD) proteins that bind RNA/DNA and exert intracellular functions in cell stress, proliferation, and differentiation. Given the pattern of DbpA staining in inflammatory glomerular diseases, without adherence to cell boundaries, we hypothesized extracellular protein occurrence and specific functions. Lipopolysaccharide and ionomycin induce DbpA expression and secretion from melanoma and mesangial cells. Unlike its homologue Y-box-binding protein 1 (YB-1), DbpA secretion requires inflammasome activation, as secretion is blocked upon the addition of a NOD-like receptor protein-3 (NLRP3) inhibitor. The addition of recombinant DbpA enhances melanoma cell proliferation, migration, and competes with tumor necrosis factor (TNF) binding to its receptor (TNFR1). In TNF-induced cell death assays, rDbpA initially blocks TNF-induced apoptosis, whereas at later time points (>24 h), cells are more prone to die. Given that CSD proteins YB-1 and DbpA fulfill the criteria of alarmins, we propose that their release signals an inherent danger to the host. Some data hint at an extracellular complex formation at a ratio of 10:1 (DbpA:YB-1) of both proteins.

DNA结合蛋白A(DbpA)属于冷休克结构域(CSD)蛋白的Y-box家族,可结合RNA/DNA,在细胞应激、增殖和分化过程中发挥细胞内功能。鉴于 DbpA 在炎症性肾小球疾病中的染色模式与细胞边界无关,我们推测它可能存在于细胞外并具有特殊功能。脂多糖和离子霉素诱导黑色素瘤和间质细胞表达和分泌 DbpA。与其同源的 Y-box 结合蛋白 1(YB-1)不同,DbpA 的分泌需要炎症小体的激活,因为在加入 NOD 样受体蛋白-3(NLRP3)抑制剂后,分泌会被阻断。加入重组 DbpA 会增强黑色素瘤细胞的增殖和迁移,并与肿瘤坏死因子(TNF)的受体(TNFR1)竞争。在 TNF 诱导的细胞死亡试验中,rDbpA 最初会阻止 TNF 诱导的细胞凋亡,而在较晚的时间点(>24 小时),细胞更容易死亡。鉴于 CSD 蛋白 YB-1 和 DbpA 符合警戒素的标准,我们认为它们的释放对宿主发出了内在危险的信号。一些数据表明,这两种蛋白以 10:1 的比例(DbpA:YB-1)形成细胞外复合物。
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引用次数: 0
Contemporaneous Inflammatory, Angiogenic, Fibrogenic, and Angiostatic Cytokine Profiles of the Time-to-Tumor Development by Cancer Cells to Orchestrate Tumor Neovascularization, Progression, and Metastasis. 癌细胞在肿瘤发展过程中同时出现的炎症、血管生成、纤维生成和血管静止细胞因子谱,可协调肿瘤血管新生、进展和转移。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-20 DOI: 10.3390/cells13201739
Elizabeth Skapinker, Emilyn B Aucoin, Haley L Kombargi, Abdulrahman M Yaish, Yunfan Li, Leili Baghaie, Myron R Szewczuk

Cytokines can promote various cancer processes, such as angiogenesis, epithelial to mesenchymal transition (EMT), invasion, and tumor progression, and maintain cancer stem-cell-like (CSCs) cells. The mechanism(s) that continuously promote(s) tumors to progress in the TME still need(s) to be investigated. The data in the present study analyzed the inflammatory, angiogenic, fibrogenic, and angiostatic cytokine profiles in the host serum during tumor development in a mouse model of human pancreatic cancer. Pancreatic MiaPaCa-2-eGFP cancer cells were subcutaneously implanted in RAG2xCγ double mutant mice. Blood samples were collected before cancer cell implantation and every week until the end point of the study. The extracted serum from the blood of each mouse at different time points during tumor development was analyzed using a Bio-Plex microarray analysis and a Bio-Plex 200 system for proinflammatory (IL-1β, IL-10, IFN-γ, and TNF-α) and angiogenic and fibrogenic (IL-15, IL-18, basic FGF, LIF, M-CSF, MIG, MIP-2, PDGF-BB, and VEGF) cytokines. Here, we find that during cancer cell colonization for tumor development, host angiogenic, fibrogenic, and proinflammatory cytokine profiling in the tumor-bearing mice has been shown to significantly reduce host angiostatic and proinflammatory cytokines that restrain tumor development and increase those for tumor growth. The proinflammatory cytokines IL-15, IL-18, and IL-1β profiles reveal a significant host serum increase after day 35 when the tumor began to progress in growth. In contrast, the angiostatic cytokine profiles of TNFα, MIG, M-CSF, IL-10, and IFNγ in the host serum revealed a dramatic and significant decrease after day 5 post-implantation of cancer cells. OP treatment of tumor-bearing mice on day 35 maintained high levels of angiostatic and fibrogenic cytokines. The data suggest an entirely new regulation by cancer cells for tumor development. The findings identify for the first time how pancreatic cancer cells use host cytokine profiling to orchestrate the initiation of tumor development.

细胞因子可促进各种癌症进程,如血管生成、上皮细胞向间质转化(EMT)、侵袭和肿瘤进展,并维持癌症干细胞样细胞(CSCs)。在TME中持续促进肿瘤进展的机制仍有待研究。本研究的数据分析了人胰腺癌小鼠模型在肿瘤发生过程中宿主血清中的炎症、血管生成、纤维化和血管抑制细胞因子谱。将胰腺 MiaPaCa-2-eGFP 癌细胞皮下植入 RAG2xCγ 双突变小鼠体内。在植入癌细胞前和研究结束前每周采集血液样本。我们使用 Bio-Plex 微阵列分析和 Bio-Plex 200 系统分析了肿瘤发生过程中不同时间点每只小鼠血液中提取的促炎细胞因子(IL-1β、IL-10、IFN-γ 和 TNF-α)以及血管生成和纤维化细胞因子(IL-15、IL-18、碱性 FGF、LIF、M-CSF、MIG、MIP-2、PDGF-BB 和 VEGF)。在此,我们发现,在癌细胞定植以促进肿瘤发展的过程中,肿瘤小鼠体内的宿主血管生成因子、纤维生成因子和促炎细胞因子谱分析显示,抑制肿瘤发展的宿主血管生成因子和促炎细胞因子显著减少,而促进肿瘤生长的宿主血管生成因子和促炎细胞因子则显著增加。促炎细胞因子 IL-15、IL-18 和 IL-1β 图谱显示,在肿瘤开始生长的第 35 天后,宿主血清中的促炎细胞因子显著增加。相比之下,宿主血清中的血管舒张细胞因子 TNFα、MIG、M-CSF、IL-10 和 IFNγ 在植入癌细胞后第 5 天显著下降。在第 35 天对肿瘤小鼠进行 OP 处理后,血管舒张细胞因子和纤维化细胞因子仍保持较高水平。这些数据表明,癌细胞对肿瘤的发展具有全新的调节作用。研究结果首次确定了胰腺癌细胞是如何利用宿主细胞因子谱来协调肿瘤发展的。
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引用次数: 0
Apolipoprotein-L1 (APOL1): From Sleeping Sickness to Kidney Disease. 载脂蛋白-L1 (APOL1):从睡病到肾病。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-20 DOI: 10.3390/cells13201738
Etienne Pays

Apolipoprotein-L1 (APOL1) is a membrane-interacting protein induced by inflammation, which confers human resistance to infection by African trypanosomes. APOL1 kills Trypanosoma brucei through induction of apoptotic-like parasite death, but two T. brucei clones acquired resistance to APOL1, allowing them to cause sleeping sickness. An APOL1 C-terminal sequence alteration, such as occurs in natural West African variants G1 and G2, restored human resistance to these clones. However, APOL1 unfolding induced by G1 or G2 mutations enhances protein hydrophobicity, resulting in kidney podocyte dysfunctions affecting renal filtration. The mechanism involved in these dysfunctions is debated. The ability of APOL1 to generate ion pores in trypanosome intracellular membranes or in synthetic membranes was provided as an explanation. However, transmembrane insertion of APOL1 strictly depends on acidic conditions, and podocyte cytopathology mainly results from secreted APOL1 activity on the plasma membrane, which occurs under non-acidic conditions. In this review, I argue that besides inactivation of APOL3 functions in membrane dynamics (fission and fusion), APOL1 variants induce inflammation-linked podocyte toxicity not through pore formation, but through plasma membrane disturbance resulting from increased interaction with cholesterol, which enhances cation channels activity. A natural mutation in the membrane-interacting domain (N264K) abrogates variant APOL1 toxicity at the expense of slightly increased sensitivity to trypanosomes, further illustrating the continuous mutual adaptation between host and parasite.

载脂蛋白-L1(APOL1)是一种由炎症诱导的膜相互作用蛋白,它使人类对非洲锥虫感染具有抵抗力。APOL1通过诱导类似凋亡的寄生虫死亡来杀死布氏锥虫,但有两个布氏锥虫克隆对APOL1产生了抗性,使它们能够引起昏睡病。APOL1 C 端序列的改变(如出现在西非天然变种 G1 和 G2 中)恢复了人类对这些克隆的抗药性。然而,G1 或 G2 突变诱导的 APOL1 解折会增强蛋白质的疏水性,从而导致肾脏荚膜细胞功能障碍,影响肾脏过滤功能。这些功能障碍所涉及的机制还存在争议。APOL1 在锥虫细胞内膜或合成膜中产生离子孔的能力被认为是一种解释。然而,APOL1 的跨膜插入严格依赖于酸性条件,而荚膜细胞病理学主要源于质膜上分泌的 APOL1 活性,它发生在非酸性条件下。在这篇综述中,我认为除了 APOL3 在膜动力学(裂变和融合)中的功能失活外,APOL1 变体诱发与炎症相关的荚膜细胞毒性不是通过孔的形成,而是通过增加与胆固醇的相互作用导致的质膜紊乱,从而增强阳离子通道的活性。膜相互作用结构域的自然突变(N264K)可消除 APOL1 变体的毒性,但对锥虫的敏感性略有增加,这进一步说明了宿主与寄生虫之间持续的相互适应。
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引用次数: 0
The Utilization of PRAME in the Diagnosis, Prognosis, and Treatment of Melanoma. 在黑色素瘤的诊断、预后和治疗中使用 PRAME。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-20 DOI: 10.3390/cells13201740
Samuel L Blount, Xiaochen Liu, Jeffrey D McBride

Melanoma, a deadly form of skin cancer, has seen improved survival rates due to advances in diagnosis and treatment, yet the need for further improvement remains critical. Tumor-associated antigens, such as PRAME (Preferentially Expressed Antigen in Melanoma), offer promising avenues for enhanced diagnostic precision, prognostic assessment, and targeted immunotherapy. PRAME, a cancer testis antigen, is selectively expressed in various cancers, including melanoma, and plays a key role in promoting tumorigenesis through inhibition of retinoic acid signaling, epithelial-to-mesenchymal transition, and immune evasion. This review explores the diagnostic utility of PRAME in distinguishing melanoma from benign nevi, its prognostic value in aggressive melanoma subtypes, and its potential as a therapeutic target in cancer vaccines and adoptive T-cell therapies. While PRAME-targeted therapies face challenges such as tumor heterogeneity and immune suppression, ongoing research aims to overcome these barriers, offering hope for more effective melanoma treatments.

黑色素瘤是一种致命的皮肤癌,由于诊断和治疗方面的进步,黑色素瘤患者的存活率有所提高,但仍亟需进一步改善。PRAME(黑色素瘤优先表达抗原)等肿瘤相关抗原为提高诊断精确度、预后评估和靶向免疫疗法提供了前景广阔的途径。PRAME是一种癌症睾丸抗原,在包括黑色素瘤在内的多种癌症中选择性表达,并通过抑制维甲酸信号传导、上皮细胞向间质转化和免疫逃避在促进肿瘤发生方面发挥着关键作用。本综述探讨了 PRAME 在区分黑色素瘤和良性痣方面的诊断作用、它在侵袭性黑色素瘤亚型中的预后价值,以及它作为癌症疫苗和免疫细胞疗法的治疗靶点的潜力。虽然PRAME靶向疗法面临着肿瘤异质性和免疫抑制等挑战,但正在进行的研究旨在克服这些障碍,为更有效的黑色素瘤治疗带来希望。
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引用次数: 0
L-PGDS-PGD2-DP1 Axis Regulates Phagocytosis by CD36+ MGs/MΦs That Are Exclusively Present Within Ischemic Areas After Stroke. L-PGDS-PGD2-DP1轴调控仅存在于脑卒中后缺血区的CD36+ MGs/MΦ的吞噬作用
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-20 DOI: 10.3390/cells13201737
Takayuki Nakagomi, Aya Narita, Hideaki Nishie, Akiko Nakano-Doi, Toshinori Sawano, Yu Fukuda, Tomohiro Matsuyama

Brain injuries, such as ischemic stroke, cause cell death. Although phagocytosis of cellular debris is mainly performed by microglia/macrophages (MGs/MΦs), excessive accumulation beyond their phagocytic capacities results in waste product buildup, delaying brain cell regeneration. Therefore, it is essential to increase the potential for waste product removal from damaged brains. Lipocalin-type prostaglandin D synthase (L-PGDS) is the primary synthase for prostaglandin D2 (PGD2) and has been reported as a scavenger of waste products. However, the mechanism by which the L-PGDS-PGD2 axis exerts such an effect remains unelucidated. In this study, using a mouse model of ischemic stroke, we found that L-PGDS and its downstream signaling pathway components, including PGD2 and PGD2 receptor DP1 (but not DP2), were significantly upregulated in ischemic areas. Immunohistochemistry revealed the predominant expression of L-PGDS in the leptomeninges of ischemic areas and high expression levels of DP1 in CD36+ MGs/MΦs that were specifically present within ischemic areas. Furthermore, PGD2 treatment promoted the conversion of MGs/MΦs into CD36+ scavenger types and increased phagocytic activities of CD36+ MGs/MΦs. Because CD36+ MGs/MΦs specifically appeared within ischemic areas after stroke, our findings suggest that the L-PGDS-PGD2-DP1 axis plays an important role in brain tissue repair by regulating phagocytic activities of CD36+ MGs/MΦs.

缺血性中风等脑损伤会导致细胞死亡。虽然细胞碎片的吞噬主要由小胶质细胞/巨噬细胞(MGs/MΦs)完成,但超出其吞噬能力的过度积累会导致废物堆积,从而延迟脑细胞再生。因此,提高受损大脑清除废物的能力至关重要。脂褐素型前列腺素 D 合成酶(L-PGDS)是前列腺素 D2(PGD2)的主要合成酶,据报道可清除废物。然而,L-PGDS-PGD2 轴发挥这种作用的机制仍未阐明。本研究利用缺血性脑卒中小鼠模型发现,L-PGDS 及其下游信号通路成分(包括 PGD2 和 PGD2 受体 DP1,但不包括 DP2)在缺血区域显著上调。免疫组化显示,L-PGDS主要表达于缺血区的脑膜,而DP1则高表达于CD36+ MGs/MΦs,这些细胞特异性地存在于缺血区。此外,PGD2 处理可促进 MGs/MΦs 转化为 CD36+ 清道夫类型,并提高 CD36+ MGs/MΦs 的吞噬活性。由于CD36+ MGs/MΦs特异性地出现在脑卒中后的缺血区域,我们的研究结果表明L-PGDS-PGD2-DP1轴通过调节CD36+ MGs/MΦs的吞噬活性在脑组织修复中发挥了重要作用。
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引用次数: 0
Excess Potassium Promotes Autophagy to Maintain the Immunosuppressive Capacity of Myeloid-Derived Suppressor Cells Independent of Arginase 1. 过量的钾促进自噬以维持髓系衍生抑制细胞的免疫抑制能力,而不依赖于精氨酸酶 1。
IF 5.1 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-19 DOI: 10.3390/cells13201736
Ramesh Thylur Puttalingaiah, Matthew J Dean, Liqin Zheng, Phaethon Philbrook, Dorota Wyczechowska, Timothy Kayes, Luis Del Valle, Denise Danos, Maria Dulfary Sanchez-Pino

Potassium ions (K+) are critical electrolytes that regulate multiple functions in immune cells. Recent studies have shown that the elevated concentration of extracellular potassium in the tumor interstitial fluid limits T cell effector function and suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). The effect of excess potassium on the biology of myeloid-derived suppressor cells (MDSCs), another important immune cell component of the tumor microenvironment (TME), is unknown. Here, we present data showing that increased concentrations of potassium chloride (KCl), as the source of K+ ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3β. Simultaneously, excess potassium ions significantly decrease the expression of arginase I (Arg I) and inducible nitric oxide synthase (iNOS) without reducing the ability of MDSCs to suppress T cell proliferation. Further investigation reveals that excess K+ ions decrease the expression of the transcription factor C/EBP-β and alter the expression of phosphorylated kinases. While excess K+ ions downregulated the expression levels of phospho-AMPKα (pAMPKα), it increased the levels of pAKT and pERK. Additionally, potassium increased mitochondrial respiration as measured by the oxygen consumption rate (OCR). Interestingly, all these alterations induced by K+ ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K+ ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs' immunosuppressive function by mechanisms independent of Arg I and iNOS. Overall, our in vitro and ex vivo findings offer valuable insights into the adaptations of MDSCs within the K+ ion-rich TME, which has important implications for MDSCs-targeted therapies.

钾离子(K+)是调节免疫细胞多种功能的重要电解质。最近的研究表明,肿瘤间质液中细胞外钾浓度升高会限制 T 细胞效应功能,并抑制肿瘤相关巨噬细胞(TAMs)的抗肿瘤能力。过量的钾对肿瘤微环境(TME)中另一种重要的免疫细胞成分--髓源性抑制细胞(MDSCs)的生物学影响尚不清楚。在此,我们提供的数据显示,氯化钾(KCl)作为 K+ 离子的来源,其浓度的增加会通过增加自噬体标记物 LC3β 的表达来促进自噬。同时,过量的钾离子会显著降低精氨酸酶 I(Arg I)和诱导型一氧化氮合酶(iNOS)的表达,而不会降低 MDSCs 抑制 T 细胞增殖的能力。进一步研究发现,过量的 K+ 离子会降低转录因子 C/EBP-β 的表达,并改变磷酸化激酶的表达。虽然过量的 K+ 离子会降低磷酸-AMPKα(pAMPKα)的表达水平,但会增加 pAKT 和 pERK 的表达水平。此外,通过耗氧率(OCR)测量,钾增加了线粒体呼吸。有趣的是,自噬抑制剂 3-甲基腺嘌呤(3-MA)可消除 K+ 离子诱导的所有这些变化。我们的研究结果表明,过量 K+ 离子引起的高渗应激通过独立于 Arg I 和 iNOS 的机制调节 MDSCs 的线粒体呼吸和信号通路,从而触发自噬过程,支持 MDSCs 的免疫抑制功能。总之,我们的体外和体内研究结果为了解 MDSCs 在富含 K+ 离子的 TME 中的适应性提供了有价值的见解,这对 MDSCs 靶向疗法具有重要意义。
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