Neutrophil Extracellular Traps Exacerbate Ischemic Brain Damage

Li, Congqin; Xing, Ying; Zhang, Yuqian; Yan, Hua; Hu, Jian; Bai, Yulong

doi:10.1007/s12035-021-02635-z

Cited by 58 publications

(35 citation statements)

References 146 publications

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“…SARS-CoV-2 can directly induce healthy neutrophils to release NETs in vitro , which increase pulmonary epithelium cell death ( 28 ). NETs also appear to drive neuroinflammation in Ischemic Brain Damage (IBD) and IBD following COVID-19, by affecting the blood-brain barrier, promoting thrombosis, and by inducing neuronal damage through extruded NETs components, NETs-IL-1 loop and IL-17 cascades ( 33 , 34 ), making them a promising target for therapy.…”

Section: Neutrophil Extracellular Trapsmentioning

confidence: 99%

Neutrophils in COVID-19: Not Innocent Bystanders

et al. 2022

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Unusually for a viral infection, the immunological phenotype of severe COVID-19 is characterised by a depleted lymphocyte and elevated neutrophil count, with the neutrophil-to-lymphocyte ratio correlating with disease severity. Neutrophils are the most abundant immune cell in the bloodstream and comprise different subpopulations with pleiotropic actions that are vital for host immunity. Unique neutrophil subpopulations vary in their capacity to mount antimicrobial responses, including NETosis (the generation of neutrophil extracellular traps), degranulation and de novo production of cytokines and chemokines. These processes play a role in antiviral immunity, but may also contribute to the local and systemic tissue damage seen in acute SARS-CoV-2 infection. Neutrophils also contribute to complications of COVID-19 such as thrombosis, acute respiratory distress syndrome and multisystem inflammatory disease in children. In this Progress review, we discuss the anti-viral and pathological roles of neutrophils in SARS-CoV-2 infection, and potential therapeutic strategies for COVID-19 that target neutrophil-mediated inflammatory responses.

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Section: Neutrophil Extracellular Trapsmentioning

confidence: 99%

Neutrophils in COVID-19: Not Innocent Bystanders

et al. 2022

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“…In patients, higher neutrophil counts are associated with more severe strokes at admission ( 91 ) and larger infarct volumes ( 87 ); while elevated neutrophil-to-lymphocyte (NLR) ratio is significantly associated with poor prognosis ( 92 ) and risk of hemorrhagic transformation ( 93 ). Although blockade of their recruitment has been shown to be neuroprotective in models of acute brain injury ( 94 ), suggesting their potential to aggravate damage, neutrophils also display beneficial roles ( 77 , 95 , 96 ). This latter evidence does not seem to apply to PC, since we observed that elevation of the number of circulating neutrophils induced after MCAo is prevented by the neuroprotective ischemic PC.…”

Section: Discussionmentioning

confidence: 99%

Ischemic Preconditioning Modulates the Peripheral Innate Immune System to Promote Anti-Inflammatory and Protective Responses in Mice Subjected to Focal Cerebral Ischemia

et al. 2022

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The development of tolerance triggered by a sublethal ischemic episode (preconditioning, PC) involves a complex crosstalk between neurons, astrocytes and microglia, although the role of the peripheral immune system in this context is largely unexplored. Here, we report that severe cerebral ischemia caused by transient middle cerebral artery occlusion (MCAo) in adult male mice elevates blood counts of inflammatory neutrophils and monocytes, and plasma levels of miRNA-329-5p. These inflammatory responses are prevented by ischemic PC induced by 15 min MCAo, 72h before the severe insult (1h MCAo). As compared with sham-operated animals, mice subjected to either ischemic PC, MCAo or a combination of both (PC+MCAo) display spleen contraction. However, protein levels of Ym1 (a marker of polarization of myeloid cells towards M2/N2 protective phenotypes) are elevated only in spleen from the experimental groups PC and PC+MCAo, but not MCAo. Conversely, Ym1 protein levels only increase in circulating leukocytes from mice subjected to 1h MCAo, but not in preconditioned animals, which is coincident with a dramatic elevation of Ym1 expression in the ipsilateral cortex. By immunofluorescence analysis, we observe that expression of Ym1 occurs in amoeboid-shaped myeloid cells, mainly representing inflammatory monocytes/macrophages and neutrophils. As a result of its immune-regulatory functions, ischemic PC prevents elevation of mRNA levels of the pro-inflammatory cytokine interleukin (IL)-1β in the ipsilateral cortex, while not affecting IL-10 mRNA increase induced by MCAo. Overall, the elevated anti-inflammatory/pro-inflammatory ratio observed in the brain of mice pre-exposed to PC is associated with reduced brain infarct volume and ischemic edema, and with amelioration of functional outcome. These findings reaffirm the crucial and dualistic role of the innate immune system in ischemic stroke pathobiology, extending these concepts to the context of ischemic tolerance and underscoring their relevance for the identification of novel therapeutic targets for effective stroke treatment.

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“…Activated neutrophils release various proteases (MMPs, elastase, cathepsin G and proteinase 3) and reactive oxygen species that strike the BBB with fatal force, allowing them to cross the endothelial layer ( 72 ). Finally, under the cascade of different chemical attractants, neutrophils reach the injured brain tissue and disrupt neural function by further disrupting the BBB through neutrophil extracellular traps and promoting thrombosis ( 64 , 73 , 74 ). Although treatment regimens targeting these molecules successfully interfere with neutrophil rolling and adhesion in animal models, they can effectively limit neutrophil accumulation and BBB leakage ( 18 ).…”

Section: The Bridgehead: Neuroinflammationmentioning

confidence: 99%

Systemic immune responses after ischemic stroke: From the center to the periphery

Liu

Zhou

et al. 2022

Front. Immunol.

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Ischemic stroke is a leading cause of disability and death. It imposes a heavy economic burden on individuals, families and society. The mortality rate of ischemic stroke has decreased with the help of thrombolytic drug therapy and intravascular intervention. However, the nerve damage caused by ischemia-reperfusion is long-lasting and followed by multiple organ dysfunction. In this process, the immune responses manifested by systemic inflammatory responses play an important role. It begins with neuroinflammation following ischemic stroke. The large number of inflammatory cells released after activation of immune cells in the lesion area, along with the deactivated neuroendocrine and autonomic nervous systems, link the center with the periphery. With the activation of systemic immunity and the emergence of immunosuppression, peripheral organs become the second “battlefield” of the immune response after ischemic stroke and gradually become dysfunctional and lead to an adverse prognosis. The purpose of this review was to describe the systemic immune responses after ischemic stroke. We hope to provide new ideas for future research and clinical treatments to improve patient outcomes and quality of life.

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Neutrophil Extracellular Traps Exacerbate Ischemic Brain Damage

Cited by 58 publications

References 146 publications

Neutrophils in COVID-19: Not Innocent Bystanders

Neutrophils in COVID-19: Not Innocent Bystanders

Ischemic Preconditioning Modulates the Peripheral Innate Immune System to Promote Anti-Inflammatory and Protective Responses in Mice Subjected to Focal Cerebral Ischemia

Systemic immune responses after ischemic stroke: From the center to the periphery

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