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

National Science Review 2023年第12期10卷 98-110页

作者： Guohao Wang Shuhan Jin Jiaqi Liu Xu Li Peng Dai Yuetong Wang Steven X.Hou The Basic Research Laboratory Center for Cancer ResearchNational Cancer Institute at FrederickNational Institutes of Health Department of Cell and Developmental Biology at the School of Life Sciences State Key Laboratory of Genetic EngineeringInstitute of Metabolism and Integrative BiologyHuman Phenome Institute Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital Fudan University

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-1β with elevated chemokines in the neuronal Arf1-ablated mouse hindbrain and spinal cord recruited and activated γ δ T cells in meninges. The activated γ δ T cells then secreted IFN-γ that 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-γ or 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 γδ T cells reactive astrocyte IFN-γ C3

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