Hyperglycemia and PPARγ Antagonistically Influence Macrophage Polarization and Infarct Healing After Ischemic Stroke.
OBJECTIVE
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.


METHODS
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.


RESULTS
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 PPARγ 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.


CONCLUSIONS
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.
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.).
Michael
M
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.).
Luisa
L
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.).
Nico
N
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.).
Hans-Peter
HP
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.). jander@uni-duesseldorf.de.
Sebastian
S
Jander
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects; D016764:Cell Polarity; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000276:immunology*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006943:Hyperglycemia / Q000150:complications / Q000276:immunology / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000276:immunology*; D007249:Inflammation; D018836:Inflammation Mediators / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000276:immunology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics*; D010644:Phenprocoumon / Q000009:adverse effects; D000077205:Pioglitazone; D012307:Risk Factors; D045162:Thiazolidinediones / Q000494:pharmacology; D066253:Vascular Remodeling / Q000187:drug effects / Q000276:immunology
D000925:Anticoagulants; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D047495:PPAR gamma; D045162:Thiazolidinediones; D010644:Phenprocoumon; D000077205:Pioglitazone
anticoagulation; cerebral ischemia; inflammation; intracerebral hemorrhage; macrophage