CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats.
CCL17 exerts neuroprotection through activation of CCR4/mTORC2 axis in microglia after subarachnoid haemorrhage in rats.
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CCL17 通过激活大鼠蛛网膜下腔出血后小胶质细胞中的 CCR4/mTORC2 轴发挥神经保护作用
DOI：
10.1136/svn-2022-001659
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发表时间：
2022-07-26
影响因子：
5.9
通讯作者：
Chen, Sheng
中科院分区：
文献类型：
--
作者：
Zhang, Anke;Liu, Yibo;Xu, Houshi;Zhang, Zeyu;Wang, Xiaoyu;Yuan, Ling;Lenahan, Cameron;Zhang, Chuan;Jiang, Junkun;Fang, Chaoyou;Fang, Yuanjian;Zhang, Jianmin;Chen, Sheng
C-C基序趋化因子配体17(CCL17)在免疫调节中发挥重要作用，在蛛网膜下腔出血(SAH)后脑损伤的病理生理过程中起重要作用。很少有证据说明CCL17在SAH中的作用。本研究试图揭示CCL17对大鼠SAH模型的治疗作用及其机制。SAH大鼠模型给予重组CCL17(RCCL17)或磷酸盐缓冲液(PBS)。应用AZD2098和JR-AB2-011研究C-C基序趋化因子受体4(CCR4)/哺乳动物靶点雷帕霉素复合体2轴(MTORC2)在CCL17介导的神经保护中的作用。为了阐明其可能的机制，我们在原代培养的小胶质细胞上进行了激活剂的测定。通过侧脑室注射腺病毒相关病毒对小胶质细胞特异性Rictor基因敲除进行治疗。进行脑组织含水量、短期神经行为评分、Western印迹分析、定量RT-PCR和组织学染色。氧合血红蛋白刺激后，CCL17的表达增加，并由神经元分泌。外源性rCCL17可显著减轻SAH大鼠神经细胞的凋亡，减轻SAH后的短期神经功能。此外，rCCL17增加了SAH后大鼠和原代培养小胶质细胞的M2样极化。抑制CCR4或mTORC2可取消rCCL17的神经保护作用。CCL17激活小胶质细胞内CCR4/mTORC2轴，可通过促进小胶质细胞M2样极化而减轻SAH所致的神经功能障碍。
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. 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. 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. CCL17 activated the CCR4/mTORC2 axis in microglia, which can alleviate SAH-induced neurological deficits by promoting M2-like polarisation of microglia.
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