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

Author:

Wang, Guohao

Jin, Shuhan

Liu, Jiaqi

Li, Xu

Dai, Peng

Wang, Yuetong

Hou, Steven X
Author Address

The Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA., 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, Shanghai200438, China.,

Abstract:

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-1ß with elevated chemokines in the neuronal Arf1-ablated mouse hindbrain and spinal cord recruited and activated gamma delta T cells in meninges. The activated gamma delta T cells then secreted IFN-gamma that entered into parenchyma to activate the microglia-A1 astrocyte-C3-neuronal C3aR neurotoxic pathway. Remarkably, the neurodegenerative phenotypes of the neuronal Arf1-ablated mice were strongly ameliorated by IFN-gamma or C3 knockout. Finally, we show that the Arf1-reduction-induced neuroimmune-IFN-gamma-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.

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