Abstract
BackgroundMacrophage migration inhibitory factor (MIF) has been proposed to play a detrimental role in stroke. We recently showed that MIF promotes neuronal death and aggravates neurological deficits during the first week after experimental stroke, in mice. Since MIF regulates tissue inflammation, we studied the putative role of MIF in post-stroke inflammation.MethodsWe subjected C57BL/6 mice, Mif-/- (MIF-KO) or Mif+/+ (WT), to a transient occlusion of the right middle cerebral artery (tMCAo) or sham-surgery. We studied MIF expression, GFAP expression and the number of CD74-positive cells in the ischemic brain hemisphere 7 days after tMCAo using primarily immunohistochemistry. We determined IFN-γ, IL-2, IL-4, IL-5, IL-10, IL-12, KC/CXCL-1 and TNF-α protein levels in the brain (48 h after surgery) and serum (48 h and 7 days after surgery) by a multiplex immunoassay.ResultsWe observed that MIF accumulates in neurons and astrocytes of the peri-infarct region, as well as in microglia/macrophages of the infarct core up to 7 days after stroke. Among the inflammatory mediators analyzed, we found a significant increase in cerebral IL-12 and KC levels after tMCAo, in comparison to sham-surgery. Importantly, the deletion of Mif did not significantly affect the levels of the cytokines evaluated, in the brain or serum. Moreover, the spleen weight 48 h and 7 days subsequent to tMCAo was similar in WT and MIF-KO mice. Finally, the extent of GFAP immunoreactivity and the number of MIF receptor (CD74)-positive cells within the ischemic brain hemisphere did not differ significantly between WT and MIF-KO mice subjected to tMCAo.ConclusionsWe conclude that MIF does not affect major components of the inflammatory/immune response during the first week after experimental stroke. Based on present and previous evidence, we propose that the deleterious MIF-mediated effects in stroke depend primarily on an intraneuronal and/or interneuronal action.
Highlights
Macrophage migration inhibitory factor (MIF) has been proposed to play a detrimental role in stroke
We previously found that Mif-/- (MIF-KO) mice have a smaller infarct volume than the respective wild-type (WT) littermates and perform significantly better when tested for sensory-motor deficits at 48 h and 7 days after transient middle cerebral artery occlusion (MCAo), [29]
Cerebral MIF expression in C57BL/6 mice 7 days after transient middle cerebral artery occlusion (tMCAo) We previously characterized the spatial-temporal expression of MIF in the brains of C57BL/6 mice up to 72 h after 45 min tMCAo
Summary
Macrophage migration inhibitory factor (MIF) has been proposed to play a detrimental role in stroke. Experimentally induced in rodents and in the clinical setting, causes an early and sustained activation of inflammatory and immune cascades, both locally in the brain and outside the brain [1]. These cascades affect cerebral cell death and neurotoxic and neuroprotective effects, depending on its exact spatial-temporal expression profile [8]. The formation of an astroglial scar, typically during the first week after stroke, is generally believed to beneficially constrain damage expansion. The inflammatory/immune response following stroke is thought to comprise an induced peripheral immunodepression [16], given for instance by a shift from T helper cell (Th) to Th2 cytokine production [17] and splenic atrophy [18]
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