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Characterizing Microglial Signaling Dynamics During Inflammation Using Single-Cell Mass Cytometry 用单细胞细胞计数技术表征炎症过程中的小胶质信号动力学。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-08 DOI: 10.1002/glia.24670
Sushanth Kumar, August D. Kahle, Austin B. Keeler, Eli R. Zunder, Christopher D. Deppmann

Microglia play a critical role in maintaining central nervous system (CNS) homeostasis and display remarkable plasticity in their response to inflammatory stimuli. However, the specific signaling profiles that microglia adopt during such challenges remain incompletely understood. Traditional transcriptomic approaches provide valuable insights, but fail to capture dynamic post-translational changes. In this study, we utilized time-resolved single-cell mass cytometry (CyTOF) to measure distinct signaling pathways activated in microglia upon exposure to bacterial and viral mimetics—lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly(I:C)), respectively. Furthermore, we evaluated the immunomodulatory role of astrocytes on microglial signaling in mixed cultures. Microglia or mixed cultures derived from neonatal mice were treated with LPS or Poly(I:C) for 48 h. Cultures were stained with a panel of 33 metal-conjugated antibodies targeting signaling and identity markers. High-dimensional clustering analysis was used to identify emergent signaling modules. We found that LPS treatment led to more robust early activation of pp38, pERK, pRSK, and pCREB compared to Poly(I:C). Despite these differences, both LPS and Poly(I:C) upregulated the classical reactivity markers CD40 and CD86 at later time points. Strikingly, the presence of astrocytes significantly blunted microglial responses to both stimuli, particularly dampening CD40 upregulation. Our studies demonstrate that single-cell mass cytometry effectively captures the dynamic signaling landscape of microglia under pro-inflammatory conditions. This approach may pave the way for targeted therapeutic investigations of various neuroinflammatory disorders. Moreover, our findings underscore the necessity of considering cellular context, such as astrocyte presence, in interpreting microglial behavior during inflammation.

小胶质细胞在维持中枢神经系统(CNS)稳态中起着至关重要的作用,并在对炎症刺激的反应中表现出显著的可塑性。然而,小胶质细胞在这些挑战中所采用的特定信号谱仍然不完全清楚。传统的转录组学方法提供了有价值的见解,但未能捕捉到动态的翻译后变化。在这项研究中,我们利用时间分辨单细胞质量细胞术(CyTOF)分别测量暴露于细菌和病毒模拟物-脂多糖(LPS)和多肌苷-多胞酸(Poly(I:C))时小胶质细胞中激活的不同信号通路。此外,我们在混合培养中评估了星形胶质细胞对小胶质细胞信号传导的免疫调节作用。用LPS或Poly(I:C)处理新生小鼠的小胶质细胞或混合培养物48小时。培养物用33种金属偶联抗体对信号和身份标记物进行染色。采用高维聚类分析识别紧急信号模块。我们发现,与Poly(I:C)相比,LPS处理导致pp38、pERK、pRSK和pCREB的早期激活更强。尽管存在这些差异,LPS和Poly(I:C)在较晚的时间点上调了经典反应性标志物CD40和CD86。引人注目的是,星形胶质细胞的存在显著减弱了小胶质细胞对这两种刺激的反应,尤其是抑制CD40上调。我们的研究表明,单细胞细胞计数术有效地捕捉了促炎条件下小胶质细胞的动态信号景观。这种方法可能为各种神经炎性疾病的靶向治疗研究铺平道路。此外,我们的研究结果强调了在解释炎症期间小胶质细胞行为时考虑细胞背景(如星形胶质细胞的存在)的必要性。
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引用次数: 0
Astrocyte Loss Augments Body Weight Through Reduction in Adipose Sympathetic Outflows 星形胶质细胞损失通过减少脂肪交感神经外流增加体重。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-08 DOI: 10.1002/glia.24673
Dan Chen, Yale Y. Yang, Yunlei Yang

Emerging evidence indicates that astrocytes modulate energy metabolism and homeostasis. However, one important but poorly understood element is the necessity of astrocytes in the control of body weight. Here, we apply viral vector-assisted brain-region selective loss of astrocytes to define physiological roles played by astrocytes in the arcuate nucleus of the hypothalamus (ARH) and to elucidate the involved mechanism. We find that astrocyte loss potently augments body weight in adult mice fed chow or high-fat diet. Mechanistically, we find that the loss of astrocytes reduces adipose tissue norepinephrine (NE) contents and chemogenetic stimulation of adipose tissue sympathetic inputs reverses the astrocyte loss-induced increase in body weight. Collectively, our findings in this study suggest a crucial physiological role of astrocytes in preventing diet-induced energy surfeit and obesity by modulating adipose tissue lipid metabolism through central sympathetic outflows to adipose tissues.

新的证据表明星形胶质细胞调节能量代谢和体内平衡。然而,星形胶质细胞在控制体重方面的必要性是一个重要但鲜为人知的因素。在此,我们利用病毒载体辅助的星形胶质细胞脑区选择性损失来定义星形胶质细胞在下丘脑弓状核(ARH)中所起的生理作用,并阐明其相关机制。我们发现星形胶质细胞的丢失能有效地增加鼠粮或高脂肪饮食的体重。从机制上讲,我们发现星形胶质细胞的丢失降低了脂肪组织去甲肾上腺素(NE)的含量,脂肪组织交感神经输入的化学发生刺激逆转了星形胶质细胞丢失引起的体重增加。总的来说,我们在这项研究中的发现表明星形胶质细胞在预防饮食引起的能量过剩和肥胖方面具有重要的生理作用,它通过中枢交感神经向脂肪组织流出调节脂肪组织脂质代谢。
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引用次数: 0
Single-Cell RNA Sequencing Uncovers Molecular Features Underlying the Disrupted Neurogenesis Following Traumatic Brain Injury 单细胞RNA测序揭示了创伤性脑损伤后神经发生中断的分子特征。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-06 DOI: 10.1002/glia.24671
Cong Liu, Fang-Hong Shao, Xuan-Cheng He, Hong-Zhen Du, Chang-Mei Liu, Bing Zhou, Zhao-Qian Teng

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with limited effective treatment strategies. Endogenous neural stem cells (NSCs) give rise to neurons and glial cells throughout life. However, NSCs are more likely to differentiate into glial cells rather than neurons at the lesion site after TBI and the underlying molecular mechanism remains largely unknown. Here, we performed large-scale single-cell transcriptome sequencing of subventricular zone (SVZ) NSCs and NSCs-derived cells in the mouse brain, and provide molecular evidence for previous observations that glial differentiation of NSCs prevails after TBI. In addition, we show that the disrupted neurogenesis following TBI is caused by the reduction of a NSC subcluster (NSC-4) expressing the neuronal gene Tubb3. Finally, we demonstrate that the transcriptional factor Dlx2 is significantly downregulated in NSC-4, and Dlx2 overexpression is sufficient to drive NSCs towards neuronal lineage differentiation at the expense of astrocytic lineage differentiation under pro-inflammatory conditions.

创伤性脑损伤(TBI)是世界范围内死亡和残疾的主要原因,有效的治疗策略有限。内源性神经干细胞(NSCs)在整个生命过程中产生神经元和神经胶质细胞。然而,创伤性脑损伤后,NSCs更有可能在损伤部位分化为胶质细胞而不是神经元,其潜在的分子机制在很大程度上仍然未知。本研究中,我们对小鼠脑室下区(SVZ) NSCs和NSCs衍生细胞进行了大规模单细胞转录组测序,并为之前观察到的脑外伤后NSCs胶质分化普遍存在的观点提供了分子证据。此外,我们发现脑外伤后的神经发生中断是由表达神经元基因Tubb3的NSC亚簇(NSC-4)减少引起的。最后,我们证明了转录因子Dlx2在NSC-4中显著下调,并且Dlx2的过表达足以在促炎条件下以星形细胞谱系分化为代价驱动NSCs向神经元谱系分化。
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引用次数: 0
Reduced White Matter Damage and Lower Neuroinflammatory Potential of Microglia and Macrophages in Hri/Eif2ak1 −/− Mice After Contusive Spinal Cord Injury 脊髓挫伤后Hri/Eif2ak1-/-小鼠脑白质损伤减少,小胶质细胞和巨噬细胞神经炎症电位降低。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-06 DOI: 10.1002/glia.24669
Sujata Saraswat Ohri, Scott A. Myers, Benjamin Rood, Brandon L. Brown, Paula M. Chilton, Lukasz Slomnicki, Yu Liu, George Z. Wei, Kariena R. Andres, Divya Mohan, Russell M. Howard, Scott R. Whittemore, Michal Hetman

Cellular stressors inhibit general protein synthesis while upregulating stress response transcripts and/or proteins. Phosphorylation of the translation factor eIF2α by one of the several stress-activated kinases is a trigger for such signaling, known as the integrated stress response (ISR). The ISR regulates cell survival and function under stress. Here, germline knockout mice were used to determine contributions by three major ISR kinases, HRI/EIF2AK1, GCN2/EIF2AK4, and PKR//EIF2AK2, to pathogenesis of moderate contusive spinal cord injury (SCI) at the thoracic T9 level. One-day post-injury (dpi), reduced levels of peIF2α were found in Hri −/− and Gcn2 −/−, but not in Pkr −/− mice. In addition, Hri −/− mice showed attenuated expression of the downstream ISR transcripts, Atf4 or Chop. Such differential effects of SCI-activated ISR correlated with a strong or moderate enhancement of locomotor recovery in Hri −/− or Gcn2 −/− mice, respectively. Hri −/− mice also showed reduced white matter loss, increased content of oligodendrocytes (OL) and attenuated neuroinflammation, including decreased lipid accumulation in microglia/macrophages. Cultured neonatal Hri −/− OLs showed lower ISR cytotoxicity. Moreover, cell autonomous reduction in neuroinflammatory potential was observed in microglia and bone marrow-derived macrophages derived from Hri −/− mice. These data identify HRI as a major positive regulator of SCI-associated secondary injury. In addition, targeting HRI may enable multimodal neuroprotection to enhance functional recovery after SCI.

细胞应激源抑制一般蛋白质合成,同时上调应激反应转录物和/或蛋白质。翻译因子eIF2α被几种应激激活激酶中的一种磷酸化是这种信号传导的触发因素,称为综合应激反应(ISR)。ISR调节应激下的细胞存活和功能。本研究使用种系敲除小鼠来确定三种主要ISR激酶HRI/EIF2AK1、GCN2/EIF2AK4和PKR//EIF2AK2在胸椎T9水平的中度挫伤脊髓损伤(SCI)发病机制中的作用。损伤后1天(dpi), Hri-/-和Gcn2-/-小鼠中peIF2α水平降低,但Pkr-/-小鼠中没有。此外,Hri-/-小鼠显示下游ISR转录本、Atf4或Chop的表达减弱。在Hri-/-或Gcn2-/-小鼠中,sci激活的ISR的这种差异效应分别与运动恢复的强烈或中度增强相关。Hri-/-小鼠还显示白质损失减少,少突胶质细胞(OL)含量增加,神经炎症减轻,包括小胶质细胞/巨噬细胞脂质积累减少。培养的新生儿Hri-/- OLs显示较低的ISR细胞毒性。此外,在Hri-/-小鼠的小胶质细胞和骨髓源性巨噬细胞中观察到神经炎症电位的细胞自主降低。这些数据确定HRI是sci相关继发性损伤的主要积极调节因子。此外,靶向HRI可能使多模式神经保护增强脊髓损伤后的功能恢复。
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引用次数: 0
Microglial Responses to Alzheimer's Disease Pathology: Insights From “Omics” Studies 小胶质细胞对阿尔茨海默病病理的反应:来自“组学”研究的见解。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-06 DOI: 10.1002/glia.24666
Aquene N. Reid, Suman Jayadev, Katherine E. Prater

Human genetics studies lent firm evidence that microglia are key to Alzheimer's disease (AD) pathogenesis over a decade ago following the identification of AD-associated genes that are expressed in a microglia-specific manner. However, while alterations in microglial morphology and gene expression are observed in human postmortem brain tissue, the mechanisms by which microglia drive and contribute to AD pathology remain ill-defined. Numerous mouse models have been developed to facilitate the disambiguation of the biological mechanisms underlying AD, incorporating amyloidosis, phosphorylated tau, or both. Over time, the use of multiple technologies including bulk tissue and single cell transcriptomics, epigenomics, spatial transcriptomics, proteomics, lipidomics, and metabolomics have shed light on the heterogeneity of microglial phenotypes and molecular patterns altered in AD mouse models. Each of these 'omics technologies provide unique information and biological insight. Here, we review the literature on the approaches and findings of these methods and provide a synthesis of the knowledge generated by applying these technologies to mouse models of AD.

十多年前,人类遗传学研究提供了确凿的证据,证明小胶质细胞是阿尔茨海默病(AD)发病机制的关键,随后发现了以小胶质细胞特异性方式表达的AD相关基因。然而,虽然在人死后脑组织中观察到小胶质细胞形态和基因表达的改变,但小胶质细胞驱动和促进阿尔茨海默病病理的机制仍不清楚。许多小鼠模型已经被开发出来,以促进对阿尔茨海默病的生物学机制的澄清,包括淀粉样变性,磷酸化tau蛋白,或两者兼而有之。随着时间的推移,多种技术的使用,包括大组织和单细胞转录组学、表观基因组学、空间转录组学、蛋白质组学、脂质组学和代谢组学,揭示了AD小鼠模型中小胶质细胞表型和分子模式改变的异质性。每一种组学技术都提供了独特的信息和生物学见解。在这里,我们回顾了有关这些方法的方法和发现的文献,并提供了将这些技术应用于AD小鼠模型所产生的知识的综合。
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引用次数: 0
Glial Biologist's Guide to Mass Spectrometry-Based Lipidomics: A Tutorial From Sample Preparation to Data Analysis 胶质生物学家的指南质谱为基础的脂质组学:教程从样品制备到数据分析。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-03 DOI: 10.1002/glia.24665
Caitlin E. Randolph, Katherine A. Walker, Ruilin Yu, Connor Beveridge, Palak Manchanda, Gaurav Chopra

Neurological diseases are associated with disruptions in the brain lipidome that are becoming central to disease pathogenesis. Traditionally perceived as static structural support in membranes, lipids are now known to be actively involved in cellular signaling, energy metabolism, and other cellular activities involving membrane curvature, fluidity, fusion or fission. Glia are critical in the development, health, and function of the brain, and glial regulation plays a major role in disease. The major pathways of glial dysregulation related to function are associated with downstream products of metabolism including lipids. Taking advantage of significant innovations and technical advancements in instrumentation, lipidomics has emerged as a popular omics discipline, serving as the prevailing approach to comprehensively define metabolic alterations associated with organismal development, damage or disease. A key technological platform for lipidomics studies is mass spectrometry (MS), as it affords large-scale profiling of complex biological samples. However, as MS-based techniques are often refined and advanced, the relative comfort level among biologists with this instrumentation has not followed suit. In this review, we aim to highlight the importance of the study of glial lipids and to provide a concise record of best practices and steps for MS-based lipidomics. Specifically, we outline procedures for glia lipidomics workflows ranging from sample collection and extraction to mass spectrometric analysis to data interpretation. To ensure these approaches are more accessible, this tutorial aims to familiarize glia biologists with sample handling and analysis techniques for MS-based lipidomics, and to guide non-experts toward generating high quality lipidomics data.

神经系统疾病与脑脂质组的破坏有关,这正在成为疾病发病机制的核心。传统上,脂质被认为是膜中的静态结构支撑,现在已知脂质积极参与细胞信号传导、能量代谢和其他涉及膜曲率、流动性、融合或裂变的细胞活动。神经胶质细胞对大脑的发育、健康和功能至关重要,神经胶质细胞的调节在疾病中起着重要作用。神经胶质功能失调的主要途径与下游代谢产物(包括脂质)有关。利用仪器的重大创新和技术进步,脂质组学已经成为一门流行的组学学科,作为全面定义与生物体发育、损伤或疾病相关的代谢改变的主流方法。质谱(MS)是脂质组学研究的一个关键技术平台,因为它提供了复杂生物样品的大规模分析。然而,由于基于质谱的技术经常被改进和先进,生物学家对这种仪器的相对舒适度并没有随之提高。在这篇综述中,我们的目的是强调胶质脂质研究的重要性,并提供一个简明的记录,以ms为基础的脂质组学的最佳实践和步骤。具体来说,我们概述了胶质脂组学工作流程的程序,从样品收集和提取到质谱分析到数据解释。为了确保这些方法更容易获得,本教程旨在使神经胶质生物学家熟悉基于质谱的脂质组学的样品处理和分析技术,并指导非专家生成高质量的脂质组学数据。
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引用次数: 0
Effect of Cytoskeletal Linker Protein GAS2L1 on Oligodendrocyte and Myelin Development 细胞骨架连接蛋白GAS2L1对少突胶质细胞和髓磷脂发育的影响。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2025-01-01 DOI: 10.1002/glia.24658
Yanping Zou, Yili Jin, Yuqian Yang, Liuning Zhang, Yuanyu Feng, Yu Long, ZhengTao Xu, Yuehua He, Wei Zheng, Shuming Wang, Yongxiang He, Jiong Li, Huiliang Li, Zhigang Luo, Chun Hu, Lin Xiao lead contact

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS), develop from OL precursor cells (OPCs) through a complex process involving significant morphological changes that are critically dependent on the dynamic interactions between cytoskeletal networks. Growth arrest-specific 2-like protein 1 (GAS2L1) is a cytoskeletal linker protein that mediates the cross-talk between actin filaments and microtubules. However, its role in OL and myelin development remains unknown. Here, we report that GAS2L1 is expressed in both OPCs and mature OLs, and that overexpression or knockdown of Gas2l1 in cultured OPCs in vitro impaired or enhanced their differentiation, respectively, while both inhibited their proliferation. We generated a Gas2l1 fl/fl mouse line and found that mice with conditional knockout of Gas2l1 in OL lineage cells (Olig1-Cre;Gas2l1 fl/fl , cKO) showed an increased number of mature OLs and enhanced myelination, as well as a reduction in the branching complexity of OPCs. In addition, an alternative mouse line with postnatally induced Gas2l1 ablation specifically in OPCs (Pdfgra-CreER T2 ;Gas2l1 fl/fl , iKO) recapitulated the acceleration of OL and myelin development as well as the inhibition of OPC process branching. Furthermore, EdU tracking in Gas2l1 iKO mice in vivo and in their OPC cultures in vitro showed both a reduction in OPC proliferation and an increase in OL maturation. Finally, cultured OPCs from iKO mice showed an increase in filopodia extension. Taken together, our results demonstrate an effect of GAS2L1 on the regulation of OL/myelin development and may provide a novel potential therapeutic target for various diseases involving OL/myelin pathology.

少突胶质细胞(OLs)是中枢神经系统(CNS)的髓磷脂形成细胞,由OL前体细胞(OPCs)发育而来,经历了一个复杂的过程,包括显著的形态学变化,这一过程严重依赖于细胞骨架网络之间的动态相互作用。生长阻滞特异性2样蛋白1 (GAS2L1)是一种细胞骨架连接蛋白,介导肌动蛋白丝和微管之间的串扰。然而,它在OL和髓鞘发育中的作用尚不清楚。在这里,我们报道了GAS2L1在OPCs和成熟的OLs中都有表达,并且在体外培养的OPCs中,GAS2L1的过表达或敲低分别会损害或增强它们的分化,而两者都抑制它们的增殖。我们建立了Gas2l1fl/fl小鼠细胞系,发现有条件敲除OL谱系细胞中的Gas2l1 (Olig1-Cre;Gas2l1fl/fl, cKO)的小鼠显示成熟OLs数量增加,髓鞘形成增强,OPCs分支复杂性降低。此外,在另一种小鼠品系(Pdfgra-CreERT2;Gas2l1fl/fl, iKO)中,出生后诱导的OPC特异性Gas2l1消融可加速OL和髓磷脂的发育,并抑制OPC过程分支。此外,在Gas2l1 iKO小鼠体内和体外OPC培养物中,EdU跟踪显示OPC增殖减少和OL成熟增加。最后,从iKO小鼠培养的OPCs显示丝足延伸增加。综上所述,我们的研究结果证明了GAS2L1对OL/髓鞘发育的调控作用,并可能为涉及OL/髓鞘病理的各种疾病提供新的潜在治疗靶点。
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引用次数: 0
WebSEQ: A New Tool for Democratizing Omics Data Sharing WebSEQ:组学数据共享民主化的新工具。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-25 DOI: 10.1002/glia.24646
Shane A. Liddelow, Ye Zhang, Steven A. Sloan

The relative ease of generation and proliferation of omics datasets has moved considerably faster than the effective dissemination of these data to the scientific community. Despite advancements in making raw data publicly available, many researchers struggle with data analysis and integration. We propose sharing analyzed data through user-friendly platforms to enhance accessibility. Here, we present a free, online tool, for sharing basic omics data in a searchable and user-friendly format. Importantly, it requires no coding or prior computational knowledge to build—only a data spreadsheet. Overall, this tool facilitates the exploration of transcriptomic, proteomic, and metabolomics data, which is crucial for understanding glial diversity and function. This initiative underscores the importance of accessible molecular data in advancing neuroscience research.

组学数据集的生成和扩散相对容易,这比这些数据在科学界的有效传播要快得多。尽管在公开原始数据方面取得了进步,但许多研究人员仍在数据分析和整合方面苦苦挣扎。我们建议通过用户友好的平台共享分析数据,以提高可访问性。在这里,我们提供了一个免费的在线工具,用于以可搜索和用户友好的格式共享基本组学数据。重要的是,它不需要编码或先前的计算知识来构建-仅需要一个数据电子表格。总的来说,该工具促进了转录组学、蛋白质组学和代谢组学数据的探索,这对于理解神经胶质多样性和功能至关重要。这一倡议强调了可访问的分子数据在推进神经科学研究中的重要性。
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引用次数: 0
Oligodendroglia Are Primed for Antigen Presentation in Response to Chronic Stress-Induced Microglial-Derived Inflammation. 在慢性应激诱导的小胶质源性炎症反应中,少突胶质细胞为抗原呈递做了准备。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-24 DOI: 10.1002/glia.24661
Miguel M Madeira, Zachary Hage, Alexandros G Kokkosis, Kimberly Nnah, Ryan Guzman, Laurel E Schappell, Dimitris Koliatsis, Emran Resutov, Neil A Nadkarni, Gilbert J Rahme, Stella E Tsirka

Chronic stress is a major contributor to the development of major depressive disorder, one of the leading causes of disability worldwide. Using a model of repeated social defeat stress in mice, we and others have reported that neuroinflammation plays a dynamic role in the development of behavioral deficits consistent with social avoidance and impaired reward responses. Animals susceptible to the model also exhibit hypomyelination in the medial prefrontal cortex, indicative of changes in the differentiation pathway of cells of the oligodendroglial lineage (OLN). We computationally confirmed the presence of immune oligodendrocytes, a population of OLN cells, which express immune markers and myelination deficits. In the current study, we report that microglia are necessary to induce expression of antigen presentation markers (and other immune markers) on oligodendroglia. We further associate the appearance of these markers with changes in the OLN and confirm that microglial changes precede OLN changes. Using co-cultures of microglia and OLN, we show that under inflammatory conditions the processes of phagocytosis and expression of MHCII are linked, suggesting potential priming for antigen presentation by OLN cells. Our findings provide insights into the nature of these OLN cells with immune capabilities, their obligatory interaction with microglia, and identify them as a potential cellular contributor to the pathological manifestations of psychosocial stress.

慢性压力是导致重度抑郁症的主要因素,而重度抑郁症是全球致残的主要原因之一。我们和其他人使用小鼠反复社交失败压力模型,报道了神经炎症在与社交回避和奖励反应受损一致的行为缺陷的发展中起着动态作用。对该模型敏感的动物也表现出内侧前额叶皮层的髓鞘退化,表明少突胶质细胞谱系(OLN)细胞分化途径的变化。我们通过计算证实了免疫少突胶质细胞的存在,这是一群表达免疫标记物和髓鞘形成缺陷的OLN细胞。在目前的研究中,我们报道了小胶质细胞是诱导抗原呈递标记(和其他免疫标记)在少突胶质细胞上表达所必需的。我们进一步将这些标记物的出现与OLN的变化联系起来,并证实小胶质细胞的变化先于OLN的变化。通过小胶质细胞和OLN的共培养,我们发现在炎症条件下,吞噬过程和MHCII的表达是相互关联的,这表明OLN细胞可能引发抗原呈递。我们的研究结果提供了对这些具有免疫能力的OLN细胞的性质的见解,它们与小胶质细胞的强制性相互作用,并确定它们是社会心理压力病理表现的潜在细胞因素。
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引用次数: 0
Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF-1R 小胶质细胞耗竭,神经炎性疾病的新工具:CSF-1R药物抑制剂的比较。
IF 5.4 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-24 DOI: 10.1002/glia.24664
David Guenoun, Nathan Blaise, Alexandre Sellam, Julie Roupret-Serzec, Alice Jacquens, Juliette Van Steenwinckel, Pierre Gressens, Cindy Bokobza

A growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro-inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF-1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF-1R. Pharmacological inhibition of CSF-1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.

越来越多的证据强调了小胶质细胞(中枢神经系统的常驻免疫细胞)的重要性,以及它们在许多神经系统疾病发病中的促炎激活。小胶质细胞的增殖、分化和存活高度依赖于CSF-1信号通路,可通过抑制其受体CSF-1R进行药理学调节。CSF-1R的药物抑制导致几乎完全的小胶质细胞耗竭,而治疗抑制则允许随后的再生。在许多神经退行性疾病(阿尔茨海默病(AD)、帕金森氏病或多发性硬化症)的动物模型中,短暂的小胶质细胞消耗减少了神经炎症,改善了行为测试结果。在这篇综述中,我们将重点比较三种不同的CSF-1R抑制剂(PLX3397, PLX5622和GW2580)对小胶质细胞耗竭的影响。我们还将强调小胶质细胞耗竭策略在成人神经疾病模型中获得的有希望的结果,并认为它们也可能在与小胶质细胞激活和神经炎症相关的神经发育疾病中证明是有希望的。最后,我们将讨论这些策略在成人和神经发育过程中对神经元、星形胶质细胞和少突胶质细胞的影响。
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引用次数: 0
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