Neutrophil Extracellular Traps in Cerebral Ischemia/Reperfusion Injury: Friend and Foe

Abstract

Cerebral ischemic injury, one of the leading causes of morbidity and mortality worldwide, triggers various central nervous system (CNS) diseases, including acute ischemic stroke (AIS) and chronic ischemia-induced Alzheimer's disease (AD). Currently, targeted therapies are urgently needed to address neurological disorders caused by cerebral ischemia/reperfusion injury (CI/RI), and the emergence of neutrophil extracellular traps (NETs) may be able to relieve the pressure. Neutrophils are precursors to brain injury following ischemic stroke and exert complicated functions. NETs extracellularly release reticular complexes of neutrophils, i.e., double-stranded DNA (dsDNA), histones, and granulins. Paradoxically, NETs play a dual role, friend and foe, under different conditions, for example, physiological circumstances, infection, neurodegeneration, and ischemia/reperfusion. Increasing evidence indicates that NETs exert anti-inflammatory effects by degrading cytokines and chemokines through protease at a relatively stable and moderate level under physiological conditions, while excessive amounts of NETs release (NETosis) irritated by CI/RI exacerbate the inflammatory response and aggravate thrombosis, disrupt the blood-brain barrier (BBB), and initiates sequential neuron injury and tissue damage. This review provides a comprehensive overview of the machinery of NETs formation and the role of an abnormal cascade of NETs in CI/RI, as well as other ischemia-induced neurological diseases. Herein, we highlight the potential of NETs as a therapeutic target against ischemic stroke that may inspire translational research and innovative clinical approaches.

Keywords: Alzheimer’s disease; CNS diseases; Ischemic stroke; cerebral ischemia; cerebral ischemia-reperfusion; neutrophil extracellular traps.

Fig. (1)

NETs formation and function after ischemic stroke. Neutrophils release neutrophil extracellular traps (NETs), extracellular reticular complexes that consist of double-stranded DNA (dsDNA), and a range of proteins in response to stimuli, such as platelet activation, interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) after ischemic stroke. Reactive oxygen species (ROS) and protein arginine deiminase 4 (PAD4) are essential for NETs formation. NETs could promote thrombus formation through different mechanisms, including platelet activation, coagulation stimulation, and constituting a scaffold for platelets to adhere. NETs are also involved in blood-brain barrier (BBB) destruction, inflammation and neuron apoptosis. And inhibition of NETs formation promotes neovascularization.

Fig. (2)

NETs in ischemia-induced Alzheimer's disease. In the AD brain, upregulated amyloid-β (Aβ) stimulates platelet activation to release HMGB1, which promotes NETs formation. Aβ, astrocytes, and microglia release ROS and proinflammatory cytokines, inducing NETs formation, which involves blood-brain barrier (BBB) destruction, inflammation, and neuron apoptosis.