CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats

Stroke and Vascular Neurology

article

Anke Zhang¹  Yibo Liu¹  Houshi Xu³  Zeyu Zhang¹  Xiaoyu Wang¹  Ling Yuan³  Cameron Lenahan⁴  Chuan Zhang⁵  Junkun Jiang⁵  Chaoyou Fang³  Yuanjian Fang¹  Jianmin Zhang¹  Sheng Chen¹ 

[1] Department of Neurosurgery , Zhejiang University School of Medicine Second Affiliated Hospital;Clinical Research Center for Neurological Diseases of Zhejiang Province;Department of Neurosurgery , Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University;Department of Biomedical Sciences , Burrell College of Osteopathic Medicine;Department of Biology , Tongji University

关键词: subarachnoid;    brain;    cerebrovascular disorders;    hemorrhage;   

DOI  :  10.1136/svn-2022-001659

学科分类：社会科学、人文和艺术（综合）

来源: BMJ Publishing Group

【 摘 要 】

Background and purpose C-C motif chemokine ligand 17 (CCL17) presents an important role in immune regulation, which is critical in the pathophysiology of brain injury after subarachnoid haemorrhage (SAH). There is rare evidence to illustrate the function of CCL17 towards SAH. In this study, we try to reveal the therapeutic effects of CCL17 and its underlying mechanism in rat SAH model.Methods SAH rat models were assigned to receive recombinant CCL17 (rCCL17) or phosphate buffer saline (PBS). AZD2098 and JR-AB2-011 were applied to investigate the C-C motif chemokine receptor 4 (CCR4)/mammalian target of rapamycin complex 2 (mTORC2) axis in CCL17-mediated neuroprotection. To elucidate the underlying mechanism, the in vitro kinase assay was performed in primary microglia. Microglial-specific Rictor knockdown was administered via intracerebroventricular injection of adenovirus-associated virus. Brain water content, short-term neurobehavioural evaluation, western blot analysis, quantitative RT-PCR and histological staining were performed.Results The expression of CCL17 was increased and secreted from neurons after oxyhaemoglobin stimulation. Exogenous rCCL17 significantly alleviated neuronal apoptosis, and alleviated short-term neurofunction after SAH in rats. In addition, rCCL17 increased M2-like polarisation of microglia in rats post-SAH and in primary microglia culture. The neuroprotection of rCCL17 was abolished via inhibition of either CCR4 or mTORC2.Conclusion CCL17 activated the CCR4/mTORC2 axis in microglia, which can alleviate SAH-induced neurological deficits by promoting M2-like polarisation of microglia.

【 授权许可】

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