A neuron-immune circuit regulates neurodegeneration in the hindbrain and spinal cord of Arf1-ablated mice  

作　　者：Guohao Wang Shuhan Jin Jiaqi Liu Xu Li Peng Dai Yuetong Wang Steven X.Hou 

机构地区：[1]Department of Cell and Developmental Biology at the School of Life Sciences,State Key Laboratory of Genetic Engineering,Institute of Metabolism and Integrative Biology,Human Phenome Institute,Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital,Fudan University,Shanghai 200438,China [2]The Basic Research Laboratory,Center for Cancer Research,National Cancer Institute at Frederick,National Institutes of Health,Frederick,MD 21702,USA

出　　处：《National Science Review》2023年第12期92-104,共13页国家科学评论（英文版）

基　　金：supported by the National Natural Science Foundation of China(92057205 and 32150710518);by the Intramural Research Program of the National Institutes of Health,National Cancer Institute,and Center for Cancer Research;supported in part by a grant from the National Multiple Sclerosis Society and Greater Bay Area Institute of Precision Medicine(Guangzhou),Fudan University,China。

摘　　要：Neuroimmune connections have been revealed to play a central role in neurodegenerative diseases(NDs).However,the mechanisms that link the central nervous system(CNS)and peripheral immune cells are still mostly unknown.We recently found that specific ablation of the Arf1 gene in hindbrain and spinal cord neurons promoted NDs through activating the NLRP3 inflammasome in microglia via peroxided lipids and adenosine triphosphate(ATP)releasing.Here,we demonstrate that IL-1βwith elevated chemokines in the neuronal Arf1-ablated mouse hindbrain and spinal cord recruited and activatedγδT cells in meninges.The activatedγδT cells then secreted IFN-γthat entered into parenchyma to activate the microglia-A1astrocyte-C3-neuronal C3a R neurotoxic pathway.Remarkably,the neurodegenerative phenotypes of the neuronal Arf1-ablated mice were strongly ameliorated by IFN-γor C3 knockout.Finally,we show that the Arf1-reduction-induced neuroimmune-IFN-γ-gliosis pathway exists in human NDs,particularly in amyotrophic lateral sclerosis and multiple sclerosis.Together,our results uncover a previously unknown mechanism that links the CNS and peripheral immune cells to promote neurodegeneration.

关 键 词：neurodegenerative diseases disease-associated microglia γδT cells reactive astrocyte IFN-γ C3 

分 类 号：R338[医药卫生—人体生理学]