Neuronal accumulation of peroxidated lipids promotes demyelination and neurodegeneration through the activation of the microglial NLRP3 inflammasome

Peroxidated lipids accumulate in the presence of reactive oxygen species and are linked to neurodegenerative diseases. Here we find that neuronal ablation of ARF1, a small GTPase important for lipid homeostasis, promoted accumulation of peroxidated lipids, lipid droplets and ATP in the mouse brain and led to neuroinflammation, demyelination and neurodegeneration, mainly in the spinal cord and hindbrain. Ablation of ARF1 in cultured primary neurons led to an increase in peroxidated lipids in co-cultured microglia, activation of the microglial NLRP3 inflammasome and release of inflammatory cytokines in an Apolipoprotein E-dependent manner. Deleting the Nlrp3 gene rescued the neurodegenerative phenotypes in the neuronal Arf1-ablated mice. We also observed a reduction in ARF1 in human brain tissue from patients with amyotrophic lateral sclerosis and multiple sclerosis. Together, our results uncover a previously unrecognized role of peroxidated lipids released from damaged neurons in activation of a neurotoxic microglial NLRP3 pathway that may play a role in human neurodegeneration. The authors demonstrate that release of peroxidated lipids from mouse neurons following ablation of the small GTPase ARF1 leads to activation of a neurotoxic microglial NLRP3 pathway and show that ARF1 is reduced in human brain tissue from patients with neurodegenerative diseases.