Single intracerebroventricular TNFR2 agonist injection impacts remyelination in the cuprizone model.

IF 4.8 3区 医学 Q1 GENETICS & HEREDITY
Valentina Pegoretti, Ate Boerema, Kim Kats, Juan M Dafauce Garcia, Roman Fischer, Roland E Kontermann, Klaus Pfizenmaier, Jon D Laman, Ulrich L M Eisel, Wia Baron
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引用次数: 0

Abstract

The development of therapeutics that enhances the regeneration of myelin sheaths following demyelination is predicted to prevent neurodegeneration. A promising target to enhance remyelination is the immunomodulatory cytokine tumor necrosis factor alpha (TNFα) and its receptors TNFR1 and TNFR2. TNFR2 on oligodendrocyte lineage cells and microglia coordinates different protective functions, such as proliferation of oligodendrocyte progenitor cells, survival of mature oligodendrocytes, and release of anti-inflammatory cytokines, in animal models of inflammation and demyelination. Here, we find in the cuprizone model that following demyelination, fewer axons are unmyelinated in the corpus callosum at an early stage of remyelination after single TNFR2 agonist delivery in the lateral ventricle, while astrocyte and microglia number and coverage are unchanged. Towards later stages of remyelination, TNFR2 agonist treatment maintains the number of oligodendrocyte lineage cells, and large caliber axons have thinner myelin. Hence, even short-term stimulation of TNFR2 has a positive impact on the remyelination processes. This study informs further on the beneficial implications of TNFR2 signaling on oligodendrocyte lineage cells and remyelination, emphasizing its potential therapeutic value for demyelinating diseases, including multiple sclerosis. KEY MESSAGES: Single TNFR2 agonist treatment in the lateral ventricle following cuprizone-induced demyelination impacts remyelination by: Leading to a lower percentage of unmyelinated axons at early stages. Preserving the number of oligodendrocyte lineage cells in the corpus callosum at later stages. Covering large calibre axons with thinner myelin sheaths at later stages.

单次脑室内注射TNFR2激动剂对铜酮模型髓鞘再生的影响。
促进脱髓鞘后髓鞘再生的治疗方法的发展被预测为防止神经退行性变。免疫调节细胞因子肿瘤坏死因子α (TNFα)及其受体TNFR1和TNFR2是促进髓鞘再生的一个有希望的靶点。在炎症和脱髓鞘动物模型中,少突胶质细胞谱系细胞和小胶质细胞上的TNFR2协调不同的保护功能,如少突胶质细胞祖细胞的增殖、成熟少突胶质细胞的存活和抗炎细胞因子的释放。在cuprizone模型中,我们发现脱髓鞘后,侧脑室单次递送TNFR2激动剂后,胼胝体在脱髓鞘早期无髓鞘的轴突减少,而星形胶质细胞和小胶质细胞的数量和覆盖范围不变。在髓鞘再生的后期,TNFR2激动剂治疗维持了少突胶质细胞系细胞的数量,并且大口径轴突具有更薄的髓鞘。因此,即使短期刺激TNFR2也会对髓鞘再生过程产生积极影响。本研究进一步揭示了TNFR2信号对少突胶质细胞谱系细胞和髓鞘再生的有益影响,强调了其对脱髓鞘疾病(包括多发性硬化症)的潜在治疗价值。关键信息:铜酮诱导脱髓鞘后,侧脑室单一TNFR2激动剂治疗通过以下方式影响髓鞘再生:导致早期无髓鞘轴突百分比降低。保留晚期胼胝体中少突胶质细胞系细胞的数量。后期被较薄的髓鞘覆盖大口径轴突。
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来源期刊
Journal of Molecular Medicine-Jmm
Journal of Molecular Medicine-Jmm 医学-医学:研究与实验
CiteScore
9.30
自引率
0.00%
发文量
100
审稿时长
1.3 months
期刊介绍: The Journal of Molecular Medicine publishes original research articles and review articles that range from basic findings in mechanisms of disease pathogenesis to therapy. The focus includes all human diseases, including but not limited to: Aging, angiogenesis, autoimmune diseases as well as other inflammatory diseases, cancer, cardiovascular diseases, development and differentiation, endocrinology, gastrointestinal diseases and hepatology, genetics and epigenetics, hematology, hypoxia research, immunology, infectious diseases, metabolic disorders, neuroscience of diseases, -omics based disease research, regenerative medicine, and stem cell research. Studies solely based on cell lines will not be considered. Studies that are based on model organisms will be considered as long as they are directly relevant to human disease.
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