2. Academic Validation
  3. 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

  • Brain Behav Immun. 2020 Oct;89:400-413. doi: 10.1016/j.bbi.2020.07.027.
Shu-Tao Xie 1,  Ao-Xue Chen 2,  Bo Song 1,  Jia Fan 1,  Wei Li 1,  Zhen Xing 1,  Shi-Yu Peng 1,  Qi-Peng Zhang 3,  Lei Dong 1,  Chao Yan 1,  Xiao-Yang Zhang 4,  Jian-Jun Wang 5,  Jing-Ning Zhu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology and Department of Physiology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China.
  • 2 Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology and Department of Physiology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China; Institute for Brain Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology and Department of Physiology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China; Institute for Brain Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China. Electronic address: xiaoyangzhang@nju.edu.cn.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology and Department of Physiology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China; Institute for Brain Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China. Electronic address: jjwang@nju.edu.cn.
  • 6 State Key Laboratory of Pharmaceutical Biotechnology and Department of Physiology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China; Institute for Brain Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China. Electronic address: jnzhu@nju.edu.cn.
PMID: 32717406 DOI: 10.1016/j.bbi.2020.07.027
Abstract

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.

Keywords

Ataxia; CCL-2; Cerebellar hemorrhage; Microglia; Purkinje cell; Stroke.

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