Suppression of microglial activation and monocyte infiltration ameliorates cerebellar hemorrhage induced-brain injury and ataxia
Suppression of microglial activation and monocyte infiltration ameliorates cerebellar hemorrhage induced-brain injury and ataxia
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抑制小胶质细胞活化和单核细胞浸润可改善小脑出血引起的脑损伤和共济失调
DOI：
10.1016/j.bbi.2020.07.027
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发表时间：
2020-10-01
影响因子：
15.1
通讯作者：
Zhu, Jing-Ning
中科院分区：
文献类型：
--
作者：
Xie, Shu-Tao;Chen, Ao-Xue;Zhu, Jing-Ning
共济失调是小脑出血（CH）患者常见的一种运动不协调的疾病，如果得不到有效的治疗，会导致长期的残疾。小胶质细胞是CNS损伤的第一反应者。但小胶质细胞在脑出血后小脑损伤和共济失调中的作用和机制尚不清楚。使用Ki 20227，一种集落刺激因子1受体的抑制剂，介导负责小胶质细胞存活的信号传导，我们确定了小胶质细胞耗竭对CH小鼠模型小脑损伤和共济失调的影响。小胶质细胞耗竭减少了小脑病变体积，减轻了步态异常，运动不协调，用米诺环素抑制CH引发的小胶质细胞活化改善了单核细胞/巨噬细胞的小脑浸润，以及产生促炎细胞因子和趋化因子C-C基序配体-2（CCL-2），其募集单核细胞/巨噬细胞。此外，米诺环素和bindarit，CCL-2抑制剂，防止浦肯野细胞，小脑皮质的主要神经元和唯一的输出的细胞凋亡和电生理功能障碍，从而改善共济失调样运动异常。我们的研究结果表明小胶质细胞在CH后的神经炎症和共济失调运动症状中起着有害作用，并为理解CH诱导的小脑共济失调的神经免疫机制铺平了新的道路。
Ataxia, characterized by uncoordinated movement, is often found in patients with cerebellar hemorrhage (CH), leading to long-term disability without effective management. Microglia are among the first responders to CNS insult. Yet the role and mechanism of microglia in cerebellar injury and ataxia after CH are still unknown. Using Ki20227, an inhibitor for colony-stimulating factor 1 receptor which mediates the signaling responsible for the survival of microglia, we determined the impact of microglial depletion on cerebellar injury and ataxia in a murine model of CH. Microglial depletion reduced cerebellar lesion volume and alleviated gait abnormality, motor incoordination, and locomotor dysfunction after CH. Suppression of CH-initiated microglial activation with minocycline ameliorated cerebellum infiltration of monocytes/macrophages, as well as production of proinflammatory cytokines and chemokine C-C motif ligand-2 (CCL-2) that recruits monocytes/macrophages. Furthermore, both minocycline and bindarit, a CCL-2 inhibitor, prevented apoptosis and electrophysiological dysfunction of Purkinje cells, the principal neurons and sole outputs of the cerebellar cortex, and consequently improved ataxia-like motor abnormalities. Our findings suggest a detrimental role of microglia in neuroinflammation and ataxic motor symptoms after CH, and pave a new path to understand the neuroimmune mechanism underlying CH-induced cerebellar ataxia.