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 evi...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.展开更多
基金Supported by Plan Andaluz de Investigacion (PAI, grupos CTS-0197 and CTS-0102)Fundacion Reina Mercedes. MA Montes-Cano is the recipient of a fellowship from Instituto de Salud Carlos III (04/0146)
基金the National Natural Science Foundation of China(81870916 and 81971107)the Fundamental Research Funds for the Central Universities,China(2019QNA7038).
文摘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.
