Neutrophils and stroke – Can neutrophils mitigate disease in the central nervous system?

• Neutrophils are first responders to injury during ischemic stroke in the CNS
• Evidence that neutrophils worsen outcomes in stroke is controversial
• Neutrophils entering a focal stroke have been shown to reduce permeability
• Neutrophils reduce permeability when applied to cultures of brain endothelium
• Over a certain threshold, neutrophils may reduce inflammation in the CNS

Neutrophils are first responders to injury in inflammatory diseases of the central nervous system (CNS) such as ischemic stroke, trauma and intracerebral hemorrhage. Studies carried out in the last three decades showed that neutrophils have mixed effects in animal models of stroke. Some studies correlated the presence of neutrophils to injury. When neutrophil infiltration was reduced by targeting CD18 or intercellular adhesion molecule-1 (ICAM-1) this generated improved outcomes. However other studies showed that when neutrophil infiltration was stimulated prior to stroke, this reduced the burden of disease. Clinical trials did not show a benefit in stroke patients from neutrophil blockade. Neutrophils may be subject to a threshold effect. When they reach a critical ratio relative to the volume of injury in the CNS, they adopt an anti-inflammatory phenotype that is able to reduce disease. When neutrophil infiltration was stimulated by injecting a stroke site in the rat with the chemokine CXCL1, this resulted in reductions in vascular permeability. Similar reductions in permeability were modeled in tissue culture models, in which neutrophils were applied to monolayers of brain endothelial cells. Neutrophils blocked the permeability increases associated with oxygen-glucose deprivation in human brain endothelial monolayers. The evidence suggests that neutrophils might adopt a pro-inflammatory N1 phenotype or an anti-inflammatory N2 phenotype in the CNS depending on environmental cues. The N2 phenotype may be adopted when neutrophil numbers exceed a critical threshold. This suggests that strategies that promote neutrophil infiltration into stroke, and other CNS inflammatory diseases, could result in improved outcomes.