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

Abstract

Background and Purpose-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

Prevalence of diabetes and its effects on stroke outcomes: A meta‐analysis and literature review

“…On a physiological and radiological level, stress hyperglycemia has been associated with a larger infarct volume on presentation, and might contribute to poorer stroke recovery through impairment of the fibrinolytic process and delayed reperfusion of the ischemic penumbra. In animal studies, stress hyperglycemia appears to induce further cerebral damage by inducing a pro‐inflammatory response, exacerbating brain edema surrounding intracranial hemorrhage, disrupting the blood–brain barrier and increasing the risk of hemorrhagic transformation.…”

Macrophage polarization in response to epigenetic modifiers during infection and inflammation

“…They signal a huge amount of M1 macrophages to rush to the site of cardiac injury to initiate cardiac remodeling [51]. Once this initial period passes, a second set comprising STAT-6, IRF-4, and PPAR-α reaches the injury site.…”

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

“…6 The classic M1 phenotype of microglia/macrophages triggers injurious responses, whereas alternatively activated M2 phenotypes scavenge debris and promote angiogenesis, tissue remodeling, and repair. [7][8][9][10][11] Intriguingly, although neutrophils have classically been regarded as detrimental, being correlated with poor histological and functional outcomes after stroke, [12][13][14][15][16] recent findings suggest that brain recruitment of N2 phenotypes may provide beneficial effects. 17,18 Thus, a strategic approach to rescue ischemic brain injury would consist in promoting polarization shifts toward M2 or N2 phenotypes, while reducing activation of pro-inflammatory phenotypes during the acute phase after stroke.…”