Mar 29, 2020

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

BioRxiv : the Preprint Server for Biology
Ivan JunierSteven X Hou


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-1{beta}, which together with elevated chemokines 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 neurotoxic pathway for destroying neurons and oligodendrocytes. Finally, we show that the Arf1-reduction-induced neuroinflammation-IFN{gamma}-gliosis pathway exists in human neurodegenerative diseases, particularly in amyotrophic lateral sclerosis and multiple sclerosis. This study illustrates perha...Continue Reading

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Mentioned in this Paper

Genome-Wide Association Study
Transcription Cofactor Activity
DNA-Directed RNA Polymerase
Transcription, Genetic
Genome Assembly Sequence
H-NS protein, bacteria

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