Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice
Sex is an important factor in the response to ischemic insults in both the laboratory and the clinic. Inflammation and cell death are points where sex-specific pathways diverge in stroke, and serum estrogen level status affect the response to inflammation. The cytokine macrophage migration inhibitor...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-06-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996113000405 |
| _version_ | 1818573208682496000 |
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| author | L. Christine Turtzo Jun Li Rebecca Persky Sharon Benashski Gillian Weston Richard Bucala Venugopal Reddy Venna Louise D. McCullough |
| author_facet | L. Christine Turtzo Jun Li Rebecca Persky Sharon Benashski Gillian Weston Richard Bucala Venugopal Reddy Venna Louise D. McCullough |
| author_sort | L. Christine Turtzo |
| collection | DOAJ |
| description | Sex is an important factor in the response to ischemic insults in both the laboratory and the clinic. Inflammation and cell death are points where sex-specific pathways diverge in stroke, and serum estrogen level status affect the response to inflammation. The cytokine macrophage migration inhibitory factor (MIF) is detrimental in experimental stroke models in male animals. However MIF is known to have sex-specific actions on inflammation and wound healing. The role of MIF in the ischemic female brain has not been evaluated. A transient middle cerebral artery occlusion (MCAO/90 min) model was used to induce stroke in male, intact female, and ovariectomized female wildtype (WT) and MIF knockout (KO) mice. Infarct size was quantified 72 h after stroke. Protein and cytokine levels were assessed post stroke. Female MIF KO mice had significantly larger strokes compared to WT females (mean hemispheric infarct±SEM: 63%±2% versus 29%±3%; n=8; p<0.05). Ovariectomized female MIF KO mice also had larger infarcts than ovariectomized WT littermates (70%±3% versus 47%±4%; n=11; p<0.05). In males, however, infarct size was equivalent between MIF KO and WT mice (63%±2% versus 67%±3%; n=9; p=0.25). There were no significant differences in cytokine levels at 6 h post-infarct between mice of either genotype in brain. MIF KO females displayed more microglial activation (ionized calcium binding adaptor molecule 1 (Iba1) immunofluorescence) after stroke than did WT mice or MIF KO males. The larger infarcts in MIF KO females were associated with an early increase in mitochondrial localization of Jun activation domain-binding protein 1 (JAB1). Loss of MIF exacerbated injury in the female brain after experimental stroke, which was independent of changes in pro-inflammatory cytokine levels. This response is sex-specific, and is in part independent of physiological serum levels of estrogen. |
| first_indexed | 2024-12-15T00:08:07Z |
| format | Article |
| id | doaj.art-1750e58bd3ed4abf9517f1a8064b301e |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-15T00:08:07Z |
| publishDate | 2013-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-1750e58bd3ed4abf9517f1a8064b301e2022-12-21T22:42:40ZengElsevierNeurobiology of Disease1095-953X2013-06-0154421431Deletion of macrophage migration inhibitory factor worsens stroke outcome in female miceL. Christine Turtzo0Jun Li1Rebecca Persky2Sharon Benashski3Gillian Weston4Richard Bucala5Venugopal Reddy Venna6Louise D. McCullough7Department of Neurology, University of Connecticut Health Center, Farmington, CT, USA; Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USADepartment of Neurology, University of Connecticut Health Center, Farmington, CT, USA; Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USADepartment of Neurology, University of Connecticut Health Center, Farmington, CT, USA; Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USADepartment of Neurology, University of Connecticut Health Center, Farmington, CT, USA; Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USADepartment of Neurology, University of Connecticut Health Center, Farmington, CT, USA; Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USADepartment of Medicine, Yale University, New Haven, CT, USA; Department of Pathology, Yale University, New Haven, CT, USADepartment of Neurology, University of Connecticut Health Center, Farmington, CT, USA; Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USADepartment of Neurology, University of Connecticut Health Center, Farmington, CT, USA; Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA; Corresponding author at: Department of Neurology, University of Connecticut Health Center, 263 Farmington Avenue, MC1840, Farmington, CT 06030, USA. Fax: +1 860 679 1181.Sex is an important factor in the response to ischemic insults in both the laboratory and the clinic. Inflammation and cell death are points where sex-specific pathways diverge in stroke, and serum estrogen level status affect the response to inflammation. The cytokine macrophage migration inhibitory factor (MIF) is detrimental in experimental stroke models in male animals. However MIF is known to have sex-specific actions on inflammation and wound healing. The role of MIF in the ischemic female brain has not been evaluated. A transient middle cerebral artery occlusion (MCAO/90 min) model was used to induce stroke in male, intact female, and ovariectomized female wildtype (WT) and MIF knockout (KO) mice. Infarct size was quantified 72 h after stroke. Protein and cytokine levels were assessed post stroke. Female MIF KO mice had significantly larger strokes compared to WT females (mean hemispheric infarct±SEM: 63%±2% versus 29%±3%; n=8; p<0.05). Ovariectomized female MIF KO mice also had larger infarcts than ovariectomized WT littermates (70%±3% versus 47%±4%; n=11; p<0.05). In males, however, infarct size was equivalent between MIF KO and WT mice (63%±2% versus 67%±3%; n=9; p=0.25). There were no significant differences in cytokine levels at 6 h post-infarct between mice of either genotype in brain. MIF KO females displayed more microglial activation (ionized calcium binding adaptor molecule 1 (Iba1) immunofluorescence) after stroke than did WT mice or MIF KO males. The larger infarcts in MIF KO females were associated with an early increase in mitochondrial localization of Jun activation domain-binding protein 1 (JAB1). Loss of MIF exacerbated injury in the female brain after experimental stroke, which was independent of changes in pro-inflammatory cytokine levels. This response is sex-specific, and is in part independent of physiological serum levels of estrogen.http://www.sciencedirect.com/science/article/pii/S0969996113000405Focal cerebral ischemiaStrokeMiddle cerebral artery occlusionMacrophage migration inhibitory factorMIFJAB1 |
| spellingShingle | L. Christine Turtzo Jun Li Rebecca Persky Sharon Benashski Gillian Weston Richard Bucala Venugopal Reddy Venna Louise D. McCullough Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice Neurobiology of Disease Focal cerebral ischemia Stroke Middle cerebral artery occlusion Macrophage migration inhibitory factor MIF JAB1 |
| title | Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice |
| title_full | Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice |
| title_fullStr | Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice |
| title_full_unstemmed | Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice |
| title_short | Deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice |
| title_sort | deletion of macrophage migration inhibitory factor worsens stroke outcome in female mice |
| topic | Focal cerebral ischemia Stroke Middle cerebral artery occlusion Macrophage migration inhibitory factor MIF JAB1 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996113000405 |
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