Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
Charité-Universitätsmedizin, 10117 Berlin, Germany.
J Neurosci. 2020 Aug 12;40(33):6428-6443. doi: 10.1523/JNEUROSCI.0666-20.2020. Epub 2020 Jul 6.
In murine experimental glioma models, TLR3 or TLR9 activation of microglial/macrophages has been shown to impair glioma growth, which could, however, not been verified in recent clinical trials. We therefore tested whether combined TLR3 and TLR9 activation of microglia/macrophages would have a synergistic effect. Indeed, combined TLR3/TLR9 activation augmented the suppression of glioma growth in organotypic brain slices from male mice in a microglia-dependent fashion, and this synergistic suppression depended on interferon β release and phagocytic tumor clearance. Combined TLR3/TLR9 stimulation also augmented several functional features of microglia, such as the release of proinflammatory factors, motility, and phagocytosis activity. TLR3/TLR9 stimulation combined with CD47 blockade further augmented glioma clearance. Finally, we confirmed that the coactivation of TLR3/TLR9 also augments the impairment of glioma growth Our results show that combined activation of TLR3/TLR9 in microglia/macrophages results in a more efficient glioma suppression, which may provide a potential strategy for glioma treatment. Glioma-associated microglia/macrophages (GAMs) are the predominant immune cells in glioma growth and are recently considered as antitumor targets. TLRs are involved in glioma growth, but the TLR3 or TLR9 ligands were not successful in clinical trials in treating glioma. We therefore combined TLR3 and TLR9 activation of GAMs, resulting in a strong synergistic effect of tumor clearance , , and Mechanisms of this GAM-glioma interaction involve IFNβ signaling and increased tumor clearance by GAMs. Interfering with CD47 signaling had an additional impact on tumor clearance. We propose that these signaling pathways could be exploited as anti-glioma targets.
在鼠类实验性神经胶质瘤模型中，已证实 TLR3 或 TLR9 激活小胶质细胞/巨噬细胞可抑制神经胶质瘤生长，但最近的临床试验未能证实这一点。因此，我们测试了小胶质细胞/巨噬细胞联合 TLR3 和 TLR9 激活是否具有协同作用。事实上，TLR3/TLR9 联合激活以依赖小胶质细胞的方式增强了雄性小鼠脑器官切片中神经胶质瘤生长的抑制作用，这种协同抑制作用依赖于干扰素-β的释放和吞噬肿瘤清除。TLR3/TLR9 联合刺激还增强了小胶质细胞的几种功能特征，如促炎因子的释放、迁移和吞噬活性。TLR3/TLR9 刺激与 CD47 阻断联合进一步增强了神经胶质瘤的清除。最后，我们证实 TLR3/TLR9 的共激活也增强了神经胶质瘤生长的损害。
我们的研究结果表明，TLR3/TLR9 在小胶质细胞/巨噬细胞中的联合激活导致更有效的神经胶质瘤抑制，这可能为神经胶质瘤的治疗提供一种潜在的策略。神经胶质瘤相关的小胶质细胞/巨噬细胞（GAMs）是神经胶质瘤生长中的主要免疫细胞，最近被认为是抗肿瘤靶点。TLRs 参与神经胶质瘤的生长，但 TLR3 或 TLR9 配体在治疗神经胶质瘤的临床试验中并未成功。因此，我们联合激活 GAMs 的 TLR3 和 TLR9，导致肿瘤清除的强烈协同作用，这表明 CD47 信号通路可能是治疗神经胶质瘤的潜在靶点。
解析：原文翻译的重点在于专业词汇和语法的理解。本文涉及了较多的医学专业词汇，如“TLR”（Toll-like receptor）、“glioma”（神经胶质瘤）、“microglia”（小胶质细胞）、“macrophages”（巨噬细胞）等，需要结合上下文进行准确理解。此外，原文中还包含了一些长难句，需要进行适当的断句和调整，以保证译文的流畅性和可读性。
