Targeting Neutrophils in Ischemic Stroke: Translational Insights from Experimental Studies

Abstract

Neutrophils have key roles in ischemic brain injury, thrombosis, and atherosclerosis. As such, neutrophils are of great interest as targets to treat and prevent ischemic stroke. After stroke, neutrophils respond rapidly promoting blood-brain barrier disruption, cerebral edema, and brain injury. A surge of neutrophil-derived reactive oxygen species, proteases, and cytokines are released as neutrophils interact with cerebral endothelium. Neutrophils also are linked to the major processes that cause ischemic stroke, thrombosis, and atherosclerosis. Thrombosis is promoted through interactions with platelets, clotting factors, and release of prothrombotic molecules. In atherosclerosis, neutrophils promote plaque formation and rupture by generating oxidized-low density lipoprotein, enhancing monocyte infiltration, and degrading the fibrous cap. In experimental studies targeting neutrophils can improve stroke. However, early human studies have been met with challenges, and suggest that selective targeting of neutrophils may be required. Several properties of neutrophil are beneficial and thus may important to preserve in patients with stroke including antimicrobial, antiinflammatory, and neuroprotective functions.

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

“…Because neutrophils are recruited at sites of cerebral ischemia and are important sources of proteases and reactive oxygen species capable of damaging the BBB, they have been previously incriminated as possible culprits contributing to BBB disruption and HT. 14,21 Furthermore, in recent years, neutrophil to lymphocyte ratio has emerged as a predictor of short-and long-term outcomes in ischemic stroke patients and of risk of HT in stroke patients treated with intravenous thrombolysis. 22 In line with this clinical data, we found that HG rats had an increase in neutrophil to lymphocyte ratio compared with NG rats.…”

“…13 Neutrophils are among the first circulating cells to respond to AIS and contribute to BBB disruption, brain edema, and HT. 14 Experimental studies revealed that hyperglycemia enhanced endothelial activation and neutrophil infiltration in the ischemic brain. 15,16 In addition, we have shown that neutrophils were central actors of proximal occlusion-induced downstream microvascular thromboinflammation (DMT), which participates to neurovascular damage in AIS.…”

Thromboinflammation in Stroke Brain Damage

“…Although neutrophil phagocytic activity may help in removing necrotic cell debris and tissue healing, the destructive nature of neutrophils is causing collateral tissue destruction, disruption of the blood-brain barrier, and cerebral edema. 58 Neutrophils contribute to cerebral injury by releasing proteolytic enzymes and free radicals that have direct neurotoxic activity. In addition, intravascular accumulation of neutrophils impairs local blood flow leading to the no-reflow phenomenon of the affected microcirculation.…”

Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

“…One explanation might be that a decrease in let7i permits a proliferation of neutrophils, a major source of plasma MMP9 post stroke. 1 However, let7i remained correlated with MMP9 when neutrophil count was adjusted for. Alternatively, MMP9 may have increased because of let7i regulation of genes that affect the production and release of MMP9.…”

“…A range of damage-associated molecular patterns, cytokines, and chemokines are released to activate circulating leukocytes, vasculature, and brain cells. 1,2 This inflammatory response has an important role in acute ischemic stroke and can contribute to the final extent of brain damage. Improved understanding of the immune response in stroke and its regulation may afford novel opportunities to optimize recovery in ischemic stroke.…”