Macrophage Migration Inhibitory Factor Alters Functional Properties of CA1 Hippocampal Neurons in Mouse Brain Slices

Abstract

Neuroinflammation is implicated in a host of neurological insults, such as traumatic brain injury (TBI), ischemic stroke, Alzheimer’s disease, Parkinson’s disease, and epilepsy. The immune response to central nervous system (CNS) injury involves sequelae including the release of numerous cytokines and chemokines. Macrophage migration inhibitory factor (MIF), is one such cytokine that is elevated following CNS injury, and is associated with the prognosis of TBI, and ischemic stroke. MIF has been identified in astrocytes and neurons, and some of the trophic actions of MIF have been related to its direct and indirect actions on astrocytes. However, the potential modulation of CNS neuronal function by MIF has not yet been explored. This study tests the hypothesis that MIF can directly influence hippocampal neuronal function. MIF was microinjected into the hippocampus and the genetically encoded calcium indicator, GCaMP6f, was used to measure Ca2+ events in acute adult mouse brain hippocampal slices. Results demonstrated that a single injection of 200 ng MIF into the hippocampus significantly increased baseline calcium signals in CA1 pyramidal neuron somata, and altered calcium responses to N-methyl-d-aspartate (NMDA) + D-serine in pyramidal cell apical dendrites located in the stratum radiatum. These data are the first to show direct effects of MIF on hippocampal neurons and on NMDA receptor function. Considering that MIF is elevated after brain insults such as TBI, the data suggest that, in addition to the previously described role of MIF in astrocyte reactivity, elevated MIF can have significant effects on neuronal function in the hippocampus.

Macrophage Migration Inhibitory Factor Promotes Expression of Matrix Metalloproteinases 1 and 3 in Spinal Cord Astrocytes following Gecko Tail Amputation

“…MIF is recognized as an important DAMPs molecule following CNS insults. It is immediately elevated after SCI by inducibly expressed in multiple cells including the neurons, oligodendrocytes, microglia, astrocytes and vascular endothelial cells, in association with neuronal apoptosis and demyelination [35,65]. Also, MIF is able to interact with membrane surface receptor CD74 in microglia and astrocytes to activate inflammatory and chemotactic responses [38,66].…”

Macrophage migration inhibitory factor in Nodding syndrome

“…In this regard, MIF was shown to affect the development and function of various cell types in the CNS, such as astrocytes, microglia and neurons. In addition, MIF is involved in different neurodegenerative diseases, including epilepsy [ 37 , 42 , 43 , 44 , 45 , 75 , 76 ]. For example, Quantitative real-time PCR (qPCR) revealed that MIF transcript gradually increases in brain during development.…”

Dualistic roles and mechanistic insights of macrophage migration inhibitory factor in brain injury and neurodegenerative diseases

“…Eric et al found that after a single injection of 200 ng exogenous MIF into the mouse hippocampus, the pharmacological kinetics of induced N-methyl-D-aspartic acid receptor (NMDA) responses in the apical dendrites of hippocampal CA1 pyramidal neurons were altered for more than two weeks, which may be responsible for sequelae after CNS injury. 52 In another rat diffuse axonal injury model, cortex MIF levels were considerably elevated 3 hours after injury and were primarily localized in neurons, intracerebroventricular injection of the MIF antagonist ISO-1 reduced neuronal apoptosis and axonal injury. 53 The similar neuronal cell death promotional effects of MIF were found to be involved in other studies, including the traumatic brain injury (TBI) model, which led to more severe neurodegeneration and neurologic deficits.…”