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Abstract
BackgroundLeukocytes contribute to tissue damage after cerebral ischemia; however, the mechanisms underlying this process are still unclear. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury.MethodsMale wild-type, ICAM-1-deficient, anti-CD18 antibody treated, or selectin-deficient [fucusyltransferase (FucT IV/VII−/−)] mice were subjected to 60 min of middle cerebral artery occlusion (MCAo). The interaction between leukocytes and the cerebrovascular endothelium was quantified by in vivo fluorescence microscopy up to 15 h thereafter. Temporal dynamics of neuronal cell death and leukocyte migration were assessed at the same time points and in the same tissue volume by histology.ResultsIn wild-type mice, leukocytes started to firmly adhere to the wall of pial postcapillary venules two hours after reperfusion. Three hours later, neuronal loss started and 13 h later, leukocytes transmigrated into brain tissue. Loss of selectin function did not influence this process. Application of an anti-CD18 antibody or genetic deletion of ICAM-1, however, significantly reduced tight adhesion of leukocytes to the cerebrovascular endothelium (-60%; p < 0.01) and increased the number of viable neurons in the ischemic penumbra by 5-fold (p < 0.01); the number of intraparenchymal leukocytes was not affected.ConclusionsOur findings suggest that ischemia triggers only a transient adhesion of leukocytes to the venous endothelium and that inhibition of this process is sufficient to partly prevent ischemic tissue damage.
Highlights
Ischemic stroke is one of the most frequent causes of death and disability worldwide [1, 2]
A plethora of elegant experimental and clinical studies discovered that ischemia triggers an acute innate immune response within the brain parenchyma which results in the production of inflammatory cytokines, the upregulation of adhesion molecules on endothelial cells, and the subsequent recruitment of granulocytes and monocytes into ischemic tissue within the first few hours and days after vessel occlusion [12,13,14,15,16,17,18,19]
We still do not know whether leukocytes are present in the brain when ischemic damage occurs or whether leukocytes are present at the site of injury [6, 7, 17, 19,20,21, 52,53,54,55,56,57]. To answer these two important issues, we investigated the full-time course and sequence of leukocyte accumulation to the ischemic brain in parallel with neuronal cell death and tried to decipher which part of the leukocyte adhesion cascade may be involved in ischemic tissue damage
Summary
Ischemic stroke is one of the most frequent causes of death and disability worldwide [1, 2]. A plethora of elegant experimental and clinical studies discovered that ischemia triggers an acute innate immune response within the brain parenchyma which results in the production of inflammatory cytokines, the upregulation of adhesion molecules on endothelial cells, and the subsequent recruitment of granulocytes and monocytes into ischemic tissue within the first few hours and days after vessel occlusion [12,13,14,15,16,17,18,19]. Tlymphocytes invade the infarcted tissue and may cause further damage [20,21,22]. Despite these impressive steps forward in our understanding of postischemic inflammation, none of the abovementioned mechanisms translated into a viable therapeutic approach for stroke patients [14]. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury
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