Macrophage Migration Inhibitory Factor Promotes Cell Death and Aggravates Neurologic Deficits after Experimental Stroke

Abstract

Multiple mechanisms contribute to tissue demise and functional recovery after stroke. We studied the involvement of macrophage migration inhibitory factor (MIF) in cell death and development of neurologic deficits after experimental stroke. Macrophage migration inhibitory factor is upregulated in the brain after cerebral ischemia, and disruption of the Mif gene in mice leads to a smaller infarct volume and better sensory-motor function after transient middle cerebral artery occlusion (tMCAo). In mice subjected to tMCAo, we found that MIF accumulates in neurons of the peri-infarct region, particularly in cortical parvalbumin-positive interneurons. Likewise, in cultured cortical neurons exposed to oxygen and glucose deprivation, MIF levels increase, and inhibition of MIF by (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) protects against cell death. Deletion of MIF in Mif À/À mice does not affect interleukin-1b protein levels in the brain and serum after tMCAo. Furthermore, disruption of the Mif gene in mice does not affect CD68, but it is associated with higher galectin-3 immunoreactivity in the brain after tMCAo, suggesting that MIF affects the molecular/cellular composition of the macrophages/microglia response after experimental stroke. We conclude that MIF promotes neuronal death and aggravates neurologic deficits after experimental stroke, which implicates MIF in the pathogenesis of neuronal injury after stroke.

A nuclease that mediates cell death induced by DNA damage and poly(ADP-ribose) polymerase-1

“…Despite the similar intensity of the ischemic insult (fig. S16C), infarct volume as previously reported (34) was reduced in MIF knockout mice in the cortex, striatum, and hemisphere by about 75% compared to that in their wild-type counterparts (Fig. 7, A to D).…”

“…It functions as a nonclassically secreted cytokine and may play important roles in cancer biology, immune responses, and inflammation (18, 37). MIF also has important roles in cellular stress and apoptosis (34, 38, 39). How MIF's nuclease activity relates to its role in the immune system and its other actions requires future studies.…”

Macrophage migration inhibitory factor deficiency protects pancreatic islets from palmitic acid‐induced apoptosis

“…[31][32][33] However, MIF acts as a pro-apoptotic molecule as well through engaging mitochondriarelated apoptotic pathway. [25][26][27][28] The initial step in the apoptosis induction is assembling of BAX molecules into large homo-oligomers that damage the outer mitochondrial membrane, consequently becoming permeable to proteins normally constrained within the intermembrane space of the mitochondria. On the other hand, presence of Bcl-2 proteins confronts membrane pore formation.…”

“…23 There is also evidence that MIF promotes apoptotic cell death in primary bladder muscle cells, B lymphocytes, tumor cell lines, cardiomyocytes and neurons. [24][25][26][27] The mechanism of apoptosis induction by MIF is not well understood. There is some circumstantial evidence that suggests the involvement of mitochondrial dysfunction in MIF-mediated apoptosis.…”

Discovery of Novel Inhibitors of the Tautomerase Activity of Macrophage Migration Inhibitory Factor (MIF)

“…5 More recently, it has been found that MIF is constitutively expressed in neurons, and that its expression levels are inversely correlated with neuronal survival after injury, oxygen-glucose deprivation, or neurotoxic insult. 6,7 It is upregulated in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, 8 stroke, 9 spinal chord injury, 6 and Alzheimer's disease. 10 In amyotrophic lateral sclerosis (ALS), there are two ways in which MIF might contribute to disease progression.…”