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

Guohao Wang; Shuhan Jin; Jiaqi Liu; Xu Li; Peng Dai; Yuetong Wang; Steven X Hou

doi:10.1093/nsr/nwad222

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

Natl Sci Rev. 2023 Aug 18;10(12):nwad222. doi: 10.1093/nsr/nwad222. eCollection 2023 Dec.

Authors

Guohao Wang¹, Shuhan Jin², Jiaqi Liu², Xu Li², Peng Dai², Yuetong Wang², Steven X Hou^{2

1}

Affiliations

¹ The Basic Research Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD 21702, USA.
² 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-1β with elevated chemokines in the neuronal Arf1-ablated mouse hindbrain and spinal cord recruited and activated γδ T cells in meninges. The activated γδ T cells then secreted IFN-γ 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-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.

Keywords: C3; IFN-γ; disease-associated microglia; neurodegenerative diseases; reactive astrocyte; γδ T cells.