The Role of Leukocytes Following Cerebral Ischemia: Pathogenic Variable or Bystander Reaction to Emerging Infarct?

Emerich, Dwaine F.; Dean, Reginald L.; Bartus, Raymond T.

doi:10.1006/exnr.2001.7835

Cited by 156 publications

(128 citation statements)

References 86 publications

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“…This effect may have resulted indirectly from a Slit-induced decrease in leukocyte chemotaxis and recruitment, and/or directly from a Slitinduced change in the neuronal response to ischemia. Although not a universal finding (Hayward et al, 1996;Emerich et al, 2002), considerable evidence supports the notion that adherent and infiltrating leukocytes contribute to ischemic damage following focal ischemia (see Jean et al, 1998 andWang et al, 2005 for reviews). In particular, the degree of leukocyte infiltration following focal stroke correlates with the severity of neuronal injury and neurological deficits in animals Clark et al, 1994;del Zoppo et al, 1991) and humans (Akopov et al, 1996).…”

Section: Discussionmentioning

confidence: 97%

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Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Altay

McLaughlin

et al. 2007

Experimental Neurology

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Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFα application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygenglucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFα and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFα. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy.

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Section: Discussionmentioning

confidence: 97%

“…Several interventions that directly or indirectly reduce inflammation improve outcome in the setting of global ischemia (Lee et al, 1999;Block et al, 2001;Ueda et al, 2005). On the other hand, leukocyte-directed therapies do not always provide benefit in global ischemia models (Aspey et al, 1989;Schott et al, 1989;Emerich et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Altay

McLaughlin

et al. 2007

Experimental Neurology

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“…However, there is evidence against a detrimental role of neutrophils in the brain after acute stroke in that neutrophil depletion does not reduce infarct volume (Beray-Berthat et al, 2003;Harris et al, 2005;Yilmaz et al, 2006). Neutrophils instead seem to enter the brain because of damage rather than being a cause of it (Emerich et al, 2002), and this does not occur to a significant degree for at least 3 days after stroke (Gelderblom et al, 2009). We did detect a reduction in both circulating and splenic monocytes and neutrophils after I-R, although no gender difference Gender, reperfusion, Nox2, and T lymphocytes after stroke VH Brait et al was present (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Contributing to Cerebral Infarct Size after Stroke: Gender, Reperfusion, T Lymphocytes, and Nox2-Derived Superoxide

Brait

Jackman

Walduck

et al. 2010

J Cereb Blood Flow Metab

140

133

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Cerebral infarct volume is typically smaller in premenopausal females than in age-matched males after ischemic stroke, but the underlying mechanisms are poorly understood. In this study we provide evidence in mice that this gender difference only occurs when the ischemic brain is reperfused. The limited tissue salvage achieved by reperfusion in male mice is associated with increased expression of proinflammatory proteins, including cyclooxygenase-2 (Cox-2), Nox2, and vascular cell adhesion molecule-1 (VCAM-1), and infiltration of Nox2-containing T lymphocytes into the infarcted brain, whereas such changes are minimal in female mice after ischemia-reperfusion (I-R). Infarct volume after I-R was no greater at 72 h than at 24 h in either gender. Infarct development was Nox2 dependent in male but not in female mice, and Nox2 within the infarct was predominantly localized in T lymphocytes. Stroke resulted in an B15-fold increase in Nox2-dependent superoxide production by circulating, but not spleen-derived, T lymphocytes in male mice, and this was Bsevenfold greater than in female mice. These circulating immune cells may thus represent a major and previously unrecognized source of superoxide in the acutely ischemic and reperfused brain of males (and potentially in postmenopausal females). Our findings provide novel insights into mechanisms that could be therapeutically targeted in acute ischemic stroke patients who receive thrombolysis therapy to induce cerebral reperfusion.

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“…8 It is also remains controversial as to whether neutrophils contribute directly to secondary brain damage or are merely bystanders that mainly assist in promoting tissue repair and recovery. 11,12 Further, T lymphocytes are now understood to contribute to ischemic brain injury after reperfusion. 13,14 Thus, Rag1 À / À mice that are deficient in lymphocytes appear to be partially protected from severe histochemical and functional outcomes after cerebral ischemia and reperfusion due to the absence of T lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Immune Cell Infiltration in Malignant Middle Cerebral Artery Infarction: Comparison with Transient Cerebral Ischemia

Chu

Kim

Lee

et al. 2013

J Cereb Blood Flow Metab

187

175

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We tested whether significant leukocyte infiltration occurs in a mouse model of permanent cerebral ischemia. C57BL6/J male mice underwent either permanent (3 or 24 hours) or transient (1 or 2 hours þ 22-to 23-hour reperfusion) middle cerebral artery occlusion (MCAO). Using flow cytometry, we observed B15,000 leukocytes (CD45 þ high cells) in the ischemic hemisphere as early as 3 hours after permanent MCAO (pMCAO), comprising B40% lymphoid cells and B60% myeloid cells. Neutrophils were the predominant cell type entering the brain, and were increased to B5,000 as early as 3 hours after pMCAO. Several cell types (monocytes, macrophages, B lymphocytes, CD8þ T lymphocytes, and natural killer cells) were also increased at 3 hours to levels sustained for 24 hours, whereas others (CD4 þ T cells, natural killer T cells, and dendritic cells) were unchanged at 3 hours, but were increased by 24 hours after pMCAO. Immunohistochemical analysis revealed that leukocytes typically had entered and widely dispersed throughout the parenchyma of the infarct within 3 hours. Moreover, compared with pMCAO, there were B50% fewer infiltrating leukocytes at 24 hours after transient MCAO (tMCAO), independent of infarct size. Microglial cell numbers were bilaterally increased in both models. These findings indicate that a profound infiltration of inflammatory cells occurs in the brain early after focal ischemia, especially without reperfusion.

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The Role of Leukocytes Following Cerebral Ischemia: Pathogenic Variable or Bystander Reaction to Emerging Infarct?

Cited by 156 publications

References 86 publications

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Slit modulates cerebrovascular inflammation and mediates neuroprotection against global cerebral ischemia

Mechanisms Contributing to Cerebral Infarct Size after Stroke: Gender, Reperfusion, T Lymphocytes, and Nox2-Derived Superoxide

Immune Cell Infiltration in Malignant Middle Cerebral Artery Infarction: Comparison with Transient Cerebral Ischemia

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