Hyperglycemia and PPARγ Antagonistically Influence Macrophage Polarization and Infarct Healing After Ischemic Stroke
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- Michael Gliem
- From the Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany (M.G., H.-P.H., S.J.); Department of Neurology, University of Münster, Münster, Germany (L.K.); and Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands (N.v.R.).
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- Luisa Klotz
- From the Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany (M.G., H.-P.H., S.J.); Department of Neurology, University of Münster, Münster, Germany (L.K.); and Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands (N.v.R.).
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- Nico van Rooijen
- From the Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany (M.G., H.-P.H., S.J.); Department of Neurology, University of Münster, Münster, Germany (L.K.); and Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands (N.v.R.).
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- Hans-Peter Hartung
- From the Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany (M.G., H.-P.H., S.J.); Department of Neurology, University of Münster, Münster, Germany (L.K.); and Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands (N.v.R.).
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- Sebastian Jander
- From the Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany (M.G., H.-P.H., S.J.); Department of Neurology, University of Münster, Münster, Germany (L.K.); and Department of Cell Biology and Immunology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands (N.v.R.).
抄録
<jats:sec> <jats:title>Background and Purpose—</jats:title> <jats:p>Secondary intracerebral hemorrhage (sICH) is a potentially serious complication of ischemic stroke, in particular under concomitant oral anticoagulation. Previous studies in murine stroke models defined a novel vascular repair function of hematogenous monocytes/macrophages (MO/MP), which proved essential for the prevention of oral anticoagulation–associated sICH. Here, we addressed the question whether hyperglycemia as a clinically relevant prohemorrhagic risk factor and peroxisome proliferator-activated receptor gamma (PPARγ) activation affect MO/MP differentiation and the risk of sICH after ischemic stroke.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods—</jats:title> <jats:p>Oral anticoagulation–associated sICH was induced by phenprocoumon feeding to mice undergoing transient middle cerebral artery occlusion. Hyperglycemia was induced by streptozotocin treatment. The role of PPARγ-dependent MO/MP differentiation was addressed in mice with myeloid cell–specific PPARγ-knockout (LysM-PPARγ(KO)). Pharmacological PPARγ activation via pioglitazone was tested as a treatment option.</jats:p> </jats:sec> <jats:sec> <jats:title>Results—</jats:title> <jats:p> Hyperglycemic mice and normoglycemic LysM-PPARγ(KO) mice exhibited abnormal proinflammatory skewing of their hematogenous MO/MP response and abnormal vascular remodeling in the infarct border zone, leading to an increased rate of oral anticoagulation–associated sICH. Pharmacological PPAR <jats:bold>γ</jats:bold> activation in hyperglycemic mice corrected the inflammatory response toward an anti-inflammatory profile, stabilized neovessels in the infarct border zone, and reduced the rate of sICH. This preventive effect was dependent on the presence of macrophages, but independent from effects on blood glucose levels. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>Hyperglycemia and macrophage-specific PPARγ activation exert opposing effects on MO/MP polarization in ischemic stroke lesions and, thereby, critically determine the risk of hemorrhagic infarct transformation.</jats:p> </jats:sec>
収録刊行物
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- Stroke
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Stroke 46 (10), 2935-2942, 2015-10
Ovid Technologies (Wolters Kluwer Health)