DOI: 10.1093/nsr/nwad222 ISSN:

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
  • Multidisciplinary

Abstract

Neuroimmune connections have been revealed to play a central role in neurodegenerative diseases (NDs). However, the mechanisms that link the CNS and peripheral immune cells are still mostly unknown. We recently found that specific ablation of Arf1 gene in hindbrain and spinal cord neurons promoted NDs through activating the NLRP3 inflammasome in microglia via peroxided lipids and ATP releasing. Here, we demonstrated that IL-1β with elevated chemokines in the neuronal Arf1-ablated mouse hindbrain and spincal cord recruited and activated γδ T cells in meninges. The activated γδ T cells then secreted IFN-γ that entered into parenchyma to activate 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 uncovered a previously unknown mechanism that links CNS and peripheral immune cells to promote neurodegeneration.

More from our Archive