Arf1-Ablation-Induced Neuronal Damage Promotes Neurodegeneration Through an NLRP3 Inflammasome–Meningeal γδ T cell–IFNγ-Reactive Astrocyte Pathway

Abstract

Neurodegenerative diseases are often initiated from neuronal injury or disease and propagated through neuroinflammation and immune response. However, the mechanisms by which injured neurons induce neuroinflammation and immune response that feedback to damage neurons are largely unknown. Here, we demonstrate that Arf1 ablation in adult mouse neurons resulted in activation of a reactive microglia-A1 astrocyte-C3 pathway in the hindbrain and midbrain but not in the forebrain, which caused demyelination, axon degeneration, synapse loss, and neurodegeneration. We further find that the Arf1-ablated neurons released peroxided lipids and ATP that activated an NLRP3 inflammasome in microglia to release IL-1β, which together with elevated chemokines recruited and activated γδT cells in meninges. The activated γδ T cells then secreted IFNγ that entered into parenchyma to activate the microglia-A1 astrocyte-C3 neurotoxic pathway for destroying neurons and oligodendrocytes. Finally, we show that the Arf1-reductioninduced neuroinflammation-IFNγ-gliosis pathway exists in human neurodegenerative diseases, particularly in amyotrophic lateral sclerosis and multiple sclerosis. This study illustrates perhaps the first complete mechanism of neurodegeneration in a mouse model.Our findings introduce a new paradigm in neurodegenerative research and provide new opportunities to treat neurodegenerative disorders.