MIF Nuclease Inhibition Protects CNS Neurons following Inflammation

In its early phases, multiple sclerosis (MS) is characterized by relapses mediated by immune cell infiltration into the central nervous system, which can mostly be managed with existing therapies. However, there is concomitant axonal injury and neuronal loss associated with these exacerbations which gradually accumulate and cause worsening of disability. This neurodegenerative pathology is not directly targeted by existing therapies. The precise mechanism(s) of cell death that neurons undergo in MS remains unclear. Here we show that parthanatos, a recently described caspase-independent, DNA damage-induced cell death program contributes to neuron death in a mouse model of autoimmune neuroinflammation, experimental autoimmune encephalomyelitis (EAE). We show that DNA damage increases in neurons during EAE, and that they are progressively lost over the disease duration. Furthermore, at early timepoints the inflamed neurons express markers of parthanatos, including accumulation of cytoplasmic poly-ADP-ribose (PAR) and nuclear macrophage migration inhibitory factor (MIF). Genetic or pharmacologic blockade of the final step in parthanatos, MIF nuclease, reduces neuron loss and disease severity. Transcriptomic characterization of these neurons reveals parthanatos-dependent differences in response to EAE. Together, this work establishes parthanatos as a key mechanism of neuron cell death during neuroinflammation.