Neutrophil recruitment to the brain in mouse and human ischemic stroke

Abstract

Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il-MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, lesser neutrophil recruitment following il-MCAo, and absence of neutrophils after sham operation. Confocal microscopy identified neutrophils in the leptomeninges from 6 h after the occlusion, in the cortical basal lamina and cortical Virchow-Robin spaces from 15 h, and also in the cortical brain parenchyma at 24 h. Neutrophils showed signs of activation including histone-3 citrullination, chromatin decondensation, and extracellular projection of DNA and histones suggestive of extracellular trap formation. Perivascular neutrophils were identified within the entire cortical infarction following c-MCAo. After il-MCAo, neutrophils prevailed in the margins but not the center of the cortical infarct, and were intraluminal and less abundant in the striatum. The lack of collaterals to the striatum and a collapsed pial anastomotic network due to brain edema in large hemispheric infarctions could impair neutrophil trafficking in this model. Neutrophil extravasation at the leptomeninges was also detected in the human tissue. We concluded that neutrophils extravasate from the leptomeningeal vessels and can eventually reach the brain in experimental animal models and humans with prolonged arterial occlusion.

Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts

“…Discussing this study in an editorial (30), it was suggested that granulocyte extravasation in ischemic infarct lesions may depend on the severity of the ischemic tissue injury and the presence of a hemorrhagic component in the lesions. Perez de Puig et al supported this view by detecting extravasation of PMNs in fatal cases of human stroke lesions and in animal models and hypothesized PMNs access to the parenchyma from the perivascular space and the leptomeninges after prolonged occlusion through activation leading to NETosis (40). However, in our study, complete tissue necrosis has been seen in the center of all cases with acute lesions, and diffuse granulocyte infiltration of the lesions was also largely absent in most cases with a hemorrhagic component.…”

Thromboinflammation in Stroke Brain Damage

“…66,67 These neutrophil extracellular DNA traps have been shown to bind platelets, red blood cells, and provide a matrix for the activation of the coagulation contact pathway. 61,66 Signs of neutrophil extracellular DNA trap formation were recently described in experimental stroke, 68 and the DNA-degrading enzyme DNase-1 was shown to reduce ischemic brain injury. 69 Additional studies are needed to assess the potentially adverse prothrombotic effects of neutrophils in cerebral ischemia and reperfusion injury to better understand their thromboinflammatory role in stroke.…”

Endothelial CD36 Contributes to Postischemic Brain Injury by Promoting Neutrophil Activation via CSF3

“…Stroke remains the leading cause of disability worldwide with limited treatment options (Moskowitz et al, 2010). Whereas reestablishing cerebral perfusion with tissue plasminogen activator and/or clot-retrieval devices may improve the outcome of some patients (Campbell et al, 2015a), these interventions have a short therapeutic window or are not widely available, and, as such, can be used only in a minority of stroke patients.…”