For decades, dementia has been characterized by accumulation of waste in the brain and low-grade inflammation. Over the years, emerging studies highlighted the involvement of the immune system in neurodegenerative disease emergence and severity. Numerous studies in animal models of amyloidosis demonstrated the beneficial role of monocyte-derived macrophages in mitigating the disease, though less is known regarding tauopathy. Boosting the immune system in animal models of both amyloidosis and tauopathy, resulted in improved cognitive performance and in a reduction of pathological manifestations. However, a full understanding of the chain of events that is involved, starting from the activation of the immune system, and leading to disease mitigation, remained elusive. Here, we hypothesized that the brain-immune communication pathway that is needed to be activated to combat tauopathy involves monocyte mobilization via the C-C chemokine receptor 2 (CCR2)/CCL2 axis, and additional immune cells, such as CD4+ T cells, including FOXP3+ regulatory CD4+ T cells. We used DM-hTAU transgenic mice, a mouse model of tauopathy, and applied an approach that boosts the immune system, via blocking the inhibitory Programmed cell death protein-1 (PD-1)/PD-L1 pathway, a manipulation previously shown to alleviate disease symptoms and pathology. An anti-CCR2 monoclonal antibody (αCCR2), was used to block the CCR2 axis in a protocol that partially eliminates monocytes from the circulation at the time of anti-PD-L1 antibody (αPD-L1) injection, and for the critical period of their recruitment into the brain following treatment. Performance of DM-hTAU mice in short-term and working memory tasks, revealed that the beneficial effect of αPD-L1, assessed 1 month after a single injection, was abrogated following blockade of CCR2. This was accompanied by the loss of the beneficial effect on disease pathology, assessed by measurement of cortical aggregated human tau load using Homogeneous Time Resolved Fluorescence-based immunoassay, and by evaluation of hippocampal neuronal survival. Using both multiparametric flow cytometry, and Cytometry by Time Of Flight, we further demonstrated the accumulation of FOXP3+ regulatory CD4+ T cells in the brain, 12 days following the treatment, which was absent subsequent to CCR2 blockade. In addition, measurement of hippocampal levels of the T-cell chemoattractant, C-X-C motif chemokine ligand 12 (Cxcl12), and of inflammatory cytokines, revealed that αPD-L1 treatment reduced their expression, while blocking CCR2 reversed this effect. The CCR2/CCL2 axis is required to modify pathology using PD-L1 blockade in a mouse model of tauopathy. This modification involves, in addition to monocytes, the accumulation of FOXP3+ regulatory CD4+ T cells in the brain, and the T-cell chemoattractant, Cxcl12.

中文翻译：

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CCR2-CCL2 轴在 tauopathy 小鼠模型疾病改变中的关键作用

几十年来，痴呆症的特征是大脑中废物的积累和低度炎症。多年来，新兴研究强调了免疫系统参与神经退行性疾病的出现和严重程度。对淀粉样变性动物模型的大量研究证明了单核细胞衍生的巨噬细胞在减轻疾病方面的有益作用，尽管对 tau蛋白病知之甚少。在淀粉样变性和 tau 病变的动物模型中增强免疫系统，可改善认知能力并减少病理表现。然而，从激活免疫系统到缓解疾病，对所涉及的一系列事件的全面了解仍然难以捉摸。这里，我们假设需要被激活以对抗 tauopathy 的脑免疫通讯通路涉及通过 CC 趋化因子受体 2 (CCR2)/CCL2 轴和其他免疫细胞（例如 CD4+ T 细胞，包括 FOXP3+ 调节性 CD4+ T 细胞）动员单核细胞细胞。我们使用了 DM-hTAU 转基因小鼠，一种 tauopathy 的小鼠模型，并应用了一种通过阻断抑制性程序性细胞死亡蛋白-1 (PD-1)/PD-L1 通路来增强免疫系统的方法，该操作先前显示减轻疾病症状和病理。抗 CCR2 单克隆抗体 (αCCR2) 用于阻断 CCR2 轴，该方案在注射抗 PD-L1 抗体 (αPD-L1) 时部分消除循环中的单核细胞，并且在关键时期他们在治疗后被招募到大脑中。DM-hTAU 小鼠在短期和工作记忆任务中的表现表明，单次注射后 1 个月评估的 αPD-L1 的有益作用在 CCR2 阻断后被取消。这伴随着对疾病病理学的有益影响的丧失，通过使用基于均质时间分辨荧光的免疫测定法测量皮质聚集的人类 tau 负荷和评估海马神经元存活来评估。使用多参数流式细胞仪和飞行时间细胞仪，我们进一步证明了 FOXP3+ 调节性 CD4+ T 细胞在治疗后 12 天在大脑中的积累，而在 CCR2 阻断后没有这种情况。此外，测量 T 细胞趋化因子、CXC 基序趋化因子配体 12 (Cxcl12) 和炎性细胞因子的海马水平，揭示了αPD-L1治疗降低了它们的表达，而阻断CCR2逆转了这种作用。CCR2/CCL2 轴需要在 tau 病变小鼠模型中使用 PD-L1 阻断来改变病理学。除了单核细胞外，这种修饰还包括大脑中 FOXP3+ 调节性 CD4+ T 细胞和 T 细胞趋化因子 Cxcl12 的积累。