Antagonism of Macrophage Migration Inhibitory Factory (MIF) after Traumatic Brain Injury Ameliorates Astrocytosis and Peripheral Lymphocyte Activation and Expansion

Abstract

Traumatic brain injury (TBI) precedes the onset of epilepsy in up to 15–20% of symptomatic epilepsies and up to 5% of all epilepsy. Treatment of acquired epilepsies, including post-traumatic epilepsy (PTE), presents clinical challenges, including frequent resistance to anti-epileptic therapies. Considering that over 1.6 million Americans present with a TBI each year, PTE is an urgent clinical problem. Neuroinflammation is thought to play a major causative role in many of the post-traumatic syndromes, including PTE. Increasing evidence suggests that neuroinflammation facilitates and potentially contributes to seizure induction and propagation. The inflammatory cytokine, macrophage migration inhibitory factor (MIF), is elevated after TBI and higher levels of MIF correlate with worse post-traumatic outcomes. MIF was recently demonstrated to directly alter the firing dynamics of CA1 pyramidal neurons in the hippocampus, a structure critically involved in many types of seizures. We hypothesized that antagonizing MIF after TBI would be anti-inflammatory, anti-neuroinflammatory and neuroprotective. The results show that administering the MIF antagonist ISO1 at 30 min after TBI prevented astrocytosis but was not neuroprotective in the peri-lesion cortex. The results also show that ISO1 inhibited the TBI-induced increase in γδT cells in the gut, and the percent of B cells infiltrating into the brain. The ISO1 treatment also increased this population of B cells in the spleen. These findings are discussed with an eye towards their therapeutic potential for post-traumatic syndromes, including PTE.

γδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde

“…While in Spinal cord injury, γδ T cells are sources of producing IFN-γ to aggravate lesions in the early phase ( 125 ). Moreover, traumatic brain injury has been linked with γδ T cells in the gut, for their increasing frequency after fluid percussion injury ( 126 ). Notably, most of mechanical injury induced neuroinflammation is pathogen free in CNS, suggesting that pattern recognition receptors (PRRs) expressed on γδ T cells are important signals for their activation.…”

Post-Traumatic Seizures: A Deep-Dive Into Pathogenesis

“…They compared before and after levels of γδ T cells after ISO1 injection. The γδ T cells were low after ISO1 therapy [30].…”

Vagus Nerve Stimulation Ameliorates Cognitive Impairment and Increased Hippocampal Astrocytes in a Mouse Model of Gulf War Illness

“…GFAP-immunohistochemistry was performed to label astrocytes in coronal sections containing hippocampi. 64 , 66 - 68 Five tissue sections per mouse were incubated in CY3 fluorescently tagged GFAP antibody (1:1000, Sigma) for 24 hours at room temperature in the dark. These sections were then washed with 0.01 M PBS for 3 times.…”

“…Quantitative analysis of GFAP-labeled astrocytes was performed using a modified optical dissector method by raters blind to the condition of the mice, as previously described. 64 , 66 - 68 Briefly, slides were coded and overlain with a numbered grid. Regions of analysis within each numbered grid were selected via a random number generator.…”