Key role of the CCR2-CCL2 axis in disease modification in a mouse model of tauopathy.
Key role of the CCR2-CCL2 axis in disease modification in a mouse model of tauopathy.
复制标题
DOI：
10.1186/s13024-021-00458-z
复制
发表时间：
2021-06-25
影响因子：
15.1
通讯作者：
Schwartz M
中科院分区：
文献类型：
--
作者：
Ben-Yehuda H;Arad M;Peralta Ramos JM;Sharon E;Castellani G;Ferrera S;Cahalon L;Colaiuta SP;Salame TM;Schwartz M
几十年来，痴呆症的特点是大脑中的废物积累和低度炎症。多年来，新兴的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。在淀粉样变性的动物模型中的许多研究证明了单核细胞衍生的巨噬细胞在减轻疾病中的有益作用，尽管关于tau蛋白病知之甚少。在淀粉样变性和tau蛋白病的动物模型中增强免疫系统，导致认知表现改善和病理表现减少。然而，对从免疫系统激活到疾病缓解的一系列事件的全面理解仍然是难以捉摸的。在这里，我们假设需要被激活以对抗tau蛋白病的脑免疫通讯途径涉及通过C-C趋化因子受体2（CCR 2）/CCL 2轴的单核细胞动员，以及额外的免疫细胞，如CD 4 + T细胞，包括FOXP 3+调节性CD 4 + T细胞。我们使用了DM-hTAU转基因小鼠，一种tau蛋白病的小鼠模型，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，这种方法以前被证明可以减轻疾病症状和病理。在一项方案中，使用抗CCR 2单克隆抗体（α CCR 2）阻断CCR 2轴，该方案在抗PD-L1抗体（α PD-L1）注射时部分消除循环中的单核细胞，并在治疗后单核细胞募集至脑中的关键时期。DM-hTAU小鼠在短期和工作记忆任务中的表现显示，单次注射后1个月评估的αPD-L1的有益作用在阻断CCR 2后消失。这伴随着对疾病病理学的有益作用的丧失，通过使用基于均相时间分辨的免疫测定法测量皮质聚集的人tau负载，以及通过评估海马神经元存活来评估。使用多参数流式细胞术和飞行时间流式细胞术，我们进一步证明了治疗后12天FOXP 3+调节性CD 4 + T细胞在脑中的积累，这在CCR 2阻断后不存在。此外，对T细胞趋化因子、C-X-C基序趋化因子配体12（Cxcl 12）和炎性细胞因子的海马水平的测量显示，αPD-L1处理降低了它们的表达，而阻断CCR 2则逆转了这一效应。CCR 2/CCL 2轴是在tau蛋白病小鼠模型中使用PD-L1阻断来改变病理学所必需的。除了单核细胞外，这种修饰还涉及FOXP 3+调节性CD 4 + T细胞在脑中的积累，以及T细胞化学引诱物Cxcl 12。在线版本包含补充材料，可通过10.1186/s13024-021-00458-z获得。
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. The online version contains supplementary material available at 10.1186/s13024-021-00458-z.
登录
查看更多内容
影响因子：
30.5
作者：
Alves de Lima K;Rustenhoven J;Da Mesquita S;Wall M;Salvador AF;Smirnov I;Martelossi Cebinelli G;Mamuladze T;Baker W;Papadopoulos Z;Lopes MB;Cao WS;Xie XS;Herz J;Kipnis J
通讯作者：
Kipnis J
影响因子：
4.3
作者：
Chen H;Lau MC;Wong MT;Newell EW;Poidinger M;Chen J
通讯作者：
Chen J
DOI：
10.1093/brain/awr074
发表时间：
2011-05
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Beers DR;Henkel JS;Zhao W;Wang J;Huang A;Wen S;Liao B;Appel SH
通讯作者：
Appel SH
影响因子：
82.9
作者：
Baruch, Kuti;Deczkowska, Aleksandra;Schwartz, Michal
通讯作者：
Schwartz, Michal
HTRF：一项针对药物发现量身定制的技术 - 对理论方面和最新应用的回顾。
DOI：
10.2174/1875397300903010022
发表时间：
2009-05-28
期刊：
Current chemical genomics
影响因子：
--
作者：
Degorce F;Card A;Soh S;Trinquet E;Knapik GP;Xie B
通讯作者：
Xie B