Exacerbation of ischemic brain injury in hypercholesterolemic mice is associated with pronounced changes in peripheral and cerebral immune responses

Herz, Josephine; Hagen, Sabine I.; Bergmüller, Eileen; Sabellek, Pascal; Göthert, Joachim R.; Buer, Jan; Hansen, Wiebke; Hermann, Dirk M.; Doeppner, Thorsten R.

doi:10.1016/j.nbd.2013.10.022

Cited by 46 publications

(42 citation statements)

References 41 publications

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“…Induction of stroke was performed using the intraluminal monofilament occlusion model as described previously 4 . A detailed description is given in the Data Supplement.…”

Section: Methodsmentioning

confidence: 99%

“…Underlying mechanisms involve alterations of the blood brain barrier 3 . However, in addition to vascular pathology hyperlipidemia triggers granulocytosis 4, 6 and therefore adds another complexity to stroke-induced pathophysiology in hyperlipidemic mice hampering translation of experimental findings into clinical practice. Emerging experimental and clinical evidences suggest that inflammatory factors outside the brain markedly influence stroke susceptibility and outcome 7 .…”

Section: Introductionmentioning

confidence: 99%

“…Emerging experimental and clinical evidences suggest that inflammatory factors outside the brain markedly influence stroke susceptibility and outcome 7 . Thus, we have previously shown that the combination of genetically and dietary-induced hyperlipidemia leads to increased cerebral ischemic tissue injury which is accompanied by elevated levels of cerebral and circulating granulocytes, albeit the causal link and the functional significance of these observations still remained elusive 4 .…”

Section: Introductionmentioning

confidence: 99%

“…In view of our earlier findings 4 , we were interested whether neutrophils contribute to the exacerbation of ischemic brain injury induced by hyperlipidemia. Therefore, we investigated how the antagonization of the neutrophil-specific chemokine receptor CXCR2 by means of a selective pharmacological inhibitor or a neutralizing CXCR2 antiserum influenced ischemic brain injury and functional recovery in hyperlipidemic ApoE −/− mice, furthermore investigating consequences of CXCR2 antagonization on peripheral neutrophil homeostasis and phenotype as well as on cerebral neutrophil infiltration.…”

Section: Introductionmentioning

confidence: 99%

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Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice

Herz

Sabellek

Lane

et al. 2015

Stroke

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Background and Purpose Inflammation-related co-morbidities contribute to stroke-induced immune responses and brain damage. We previously showed that hyperlipidemia exacerbates ischemic brain injury, which is associated with elevated peripheral and cerebral granulocyte numbers. Herein, we evaluate the contribution of neutrophils to the exacerbation of ischemic brain injury. Methods Wildtype mice fed with a normal chow and ApoE knockout mice fed with a high cholesterol diet were exposed to middle cerebral artery occlusion (MCAO). CXCR2 was blocked using the selective antagonist SB225002 (2 mg/kg) or neutralizing CXCR2 antiserum. Neutrophils were depleted using an anti-Ly6G antibody. At 72 hours post-ischemia immunohistochemistry, flow cytometry and real-time PCR was performed to determine cerebral tissue injury and immunological changes in the blood, bone marrow and brain. Functional outcome was assessed by accelerated rota rod and tight rope tests at 4, 7 and 14 days post-ischemia. Results CXCR2 antagonization reduced neurological deficits and infarct volumes that were exacerbated in hyperlipidemic ApoE−/− mice. This effect was mimicked by neutrophil depletion. Cerebral neutrophil infiltration and peripheral neutrophilia, which were increased upon ischemia in hyperlipidemia, were attenuated by CXCR2 antagonization. This downscaling of neutrophil responses was associated with increased neutrophil apoptosis and reduced levels of CXCR2, iNOS and NOX2 expression on bone marrow neutrophils. Conclusion Our data demonstrate a role of neutrophils in the exacerbation of ischemic brain injury induced by hyperlipidemia. Accordingly, CXCR2 blockade, which prevents neutrophil recruitment into the brain, might be an effective option for stroke treatment in patients suffering from hyperlipidemia.

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“…Induction of stroke was performed using the intraluminal monofilament occlusion model as described previously 4 . A detailed description is given in the Data Supplement.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice

Herz

Sabellek

Lane

et al. 2015

Stroke

Self Cite

179

135

View full text Add to dashboard Cite

show abstract

“…Transient middle cerebral artery occlusion (tMCAO) was induced as described [26]. Briefly, animals were anesthetized with 1 % isoflurane (30 % O 2 , remainder N 2 O) and their rectal temperature was maintained between 36.5 and 37.0 °C using a feedback-controlled heating system (Harvard Apparatus, Heidelberg, Germany).…”

Section: Induction Of Transient Middle Cerebral Artery Occlusion and mentioning

confidence: 99%

Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke

et al. 2014

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Neuronal injury from ischemic stroke is aggravated by invading peripheral immune cells. Early infiltrates of neutrophil granulocytes and T-cells influence the outcome of stroke. So far, however, neither the timing nor the cellular dynamics of neutrophil entry, its consequences for the invaded brain area, or the relative importance of T-cells has been extensively studied in an intravital setting. Here, we have used intravital two-photon microscopy to document neutrophils and brain-resident microglia in mice after induction of experimental stroke. We demonstrated that neutrophils immediately rolled, firmly adhered, and transmigrated at sites of endothelial activation in stroke-affected brain areas. The ensuing neutrophil invasion was associated with local blood-brain barrier breakdown and infarct formation. Brain-resident microglia recognized both endothelial damage and neutrophil invasion. In a cooperative manner, they formed cytoplasmic processes to physically shield activated endothelia and trap infiltrating neutrophils. Interestingly, the systemic blockade of very-late-antigen-4 immediately and very effectively inhibited the endothelial interaction and brain entry of neutrophils. This treatment thereby strongly reduced the ischemic tissue injury and effectively protected the mice from stroke-associated behavioral impairment. Behavioral preservation was also equally well achieved with the antibody-mediated depletion of myeloid cells or specifically neutrophils. In contrast, T-cell depletion more effectively reduced the infarct volume without improving the behavioral performance. Thus, neutrophil invasion of the ischemic brain is rapid, massive, and a key mediator of functional impairment, while peripheral T-cells promote brain damage. Acutely depleting T-cells and inhibiting brain infiltration of neutrophils might, therefore, be a powerful early stroke treatment.

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Ischemic stroke, obesity, and the anti‐inflammatory role of melatonin

et al. 2020

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Obesity is a predominant risk factor in ischemic stroke and is commonly comorbid with it. Pathologies following these conditions are associated with systemic and local inflammation. Moreover, there is increasing evidence that the susceptibility for ischemic brain damage increases substantially in experimental models of ischemic stroke with concomitant obesity. Herein, we explore the proinflammatory events that occur during ischemic stroke and obesity, and we discuss the influence of obesity on the inflammatory response and cerebral damage outcomes in experimental models of brain ischemia. In addition, because melatonin is a neurohormone widely reported to exhibit protective effects in various diseases, this study also demonstrates the anti‐inflammatory role and possible mechanistic actions of melatonin in both epidemic diseases. A summary of research findings suggests that melatonin administration has great potential to exert an anti‐inflammatory role and provide protection against obesity and ischemic stroke conditions. However, the efficacy of this hormonal treatment on ischemic stroke with concomitant obesity, when more serious inflammation is generated, is still lacking.

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Exacerbation of ischemic brain injury in hypercholesterolemic mice is associated with pronounced changes in peripheral and cerebral immune responses

Cited by 46 publications

References 41 publications

Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice

Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice

Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke

Ischemic stroke, obesity, and the anti‐inflammatory role of melatonin

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