MIF Tautomerase Inhibition Protects Neurons From Immune-Mediated Cell Death

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is characterized by peripheral immune cell infiltration into the central nervous system (CNS) and associated reactive gliosis, demyelination, and neuroaxonal degeneration. Existing therapies broadly target adaptive immune cells and treat acute inflammation but are not effective in halting chronic neurodegeneration that occurs in progressive MS. High-efficacy precision therapies that target pathways in the CNS known to contribute to MS pathophysiology are lacking. Several MS studies have identified prominent dysregulation of macrophage migration inhibitory factor (MIF), a multifunctional protein with both cytokine and enzyme activity, in inflammatory diseases. MIF is elevated in the CSF of people with MS and MIF gene variants have been linked with progressive MS, but its precise contributions to the pathophysiologic underpinnings of MS remain unclear. MIF has extracellular signaling capacity through CD74. MIF also has 2 discrete and endogenous enzymatic functions as a tautomerase and nuclease. METHODS: We used a MIF transgenic mouse line with a point mutation in the tautomerase domain (MIF-P2G) to dissect MIF's non-nuclease function during inflammation. We also utilized flow cytometry and immunohistochemistry to characterize the cellular and molecular mechanisms by which MIF tautomerase contributes to pathophysiology in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. RESULTS: We show that MIF tautomerase contributes to immune cell infiltration, glial cell proliferation, and neuroaxonal degeneration in EAE. MIF tautomerase-deficient EAE mice have reduced paralysis scores and less neuroaxonal pathology throughout the optic nerve and lumbar spinal cord. Furthermore, we show that MIF-P2G mutated mice have less peripheral immune cell trafficking and downstream reactive gliosis, neuroinflammation, and neurodegeneration during EAE. DISCUSSION: Together, this work elucidates the role of MIF's tautomerase domain in contributing to peripheral immune-mediated neurodegeneration in the context of neuroinflammatory diseases such as MS.