Neutrophil Extracellular Traps may be a Potential Target for Treating Early Brain Injury in Subarachnoid Hemorrhage

Zeng, Hanhai; Fu, Xiongjie; Cai, Jing; Sun, Chenjun; Yu, Mengyan; Peng, Yucong; Zhuang, Jianfeng; Chen, Jingyin; Chen, Huaijun; Yu, Qian; Xu, Chaoran; Zhou, Hang; Cao, Yang; Hu, Libin; Li, Jianru; Cao, Shenglong; Gu, Chi; Yan, Feng; Chen, Gao

doi:10.1007/s12975-021-00909-1

Cited by 56 publications

(47 citation statements)

References 60 publications

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“…In accordance with the previous reports, our study also confirmed that animals exhibited remarkable inflammatory response in SAH (19,27,38). Microglia polarization and neutrophil infiltration have been proven to be the important mechanisms in the pathological process of SAH in multiple research centers including ours (9,14,19,(39)(40)(41). However, the upstream pathway of microglia polarization, the deep mechanism of neutrophil infiltration, and the relationship between peripheral and central immunity are relatively limited, which are also the topics that we want to explore in this study.…”

Section: Discussionsupporting

confidence: 93%

“…However, it is the first time to reported them in SAH studies. Besides, our previous articles also confirmed the role of NETs in SAH and the role of NETs in the induction of proinflammatory subtypes of microglia (17,19). In this study, we observed that TREM1 was upregulated after SAH and promote inflammation in cerebral cortex.…”

Section: Discussionsupporting

confidence: 81%

“…Neutrophil extracellular traps (NETs), a relatively well-described pathway of neutrophil induced injury, can cause tissue-damaging immunopathology in an inflammatory state ( 20 ). Our previous articles also confirmed the role of NETs in SAH and the role of NETs in the induction of proinflammatory subtypes of microglia ( 17 , 19 ). These suggests that inhibition of neuroinflammation by suppressing the formation of NETs might also be an potential therapeutic strategy for SAH management as well.…”

Section: Introductionsupporting

confidence: 79%

“…Mice were euthanized at 24 hours after surgery for IF staining, which was conducted as previously described ( 3 , 19 ). Brain sections with 8-μm thickness were incubated with 5% bovine serum albumin (BSA) and 0.3% Triton X-100 for 2 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Neutrophils are innate immune cells and play a key role in immune defense and disease pathology ( 17 ). Following the onset of SAH, neutrophils infiltrate into the brain parenchyma ( 18 , 19 ). Neutrophil extracellular traps (NETs), a relatively well-described pathway of neutrophil induced injury, can cause tissue-damaging immunopathology in an inflammatory state ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

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TREM1 Regulates Neuroinflammatory Injury by Modulate Proinflammatory Subtype Transition of Microglia and Formation of Neutrophil Extracellular Traps via Interaction With SYK in Experimental Subarachnoid Hemorrhage

Zeng

et al. 2021

Front. Immunol.

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Neuroinflammation is a key process in the pathogenesis of subarachnoid hemorrhage (SAH) and contributes to poor outcome in patients. The purpose of this study is to explore the effect of triggering receptor expressed on myeloid cells 1 (TREM1) in the SAH, as well as its potential mechanism. In our study, plasma levels of soluble TREM1 was increased significantly after SAH and correlated to SAH severity and serum C-reactiveprotein. TREM1 inhibitory peptide LP17 alleviated the neurological deficits, attenuated brain water content, and reduced neuronal damage after SAH. Meanwhile, TREM1 inhibitory peptide decreased neuroinflammation (evidenced by the decreased levels of markers including IL-6, IL-1β, TNF-α) by attenuating proinflammatory subtype transition of microglia (evidenced by the decreased levels of markers including CD68, CD16, CD86) and decreasing the formation of neutrophil extracellular traps (evidenced by the decreased levels of markers including CitH3, MPO, and NE). Further mechanistic study identified that TREM1 can activate downstream proinflammatory pathways through interacting with spleen tyrosine kinase (SYK). In conclusion, inhibition of TREM1 alleviates neuroinflammation by attenuating proinflammatory subtype transition of microglia and decreasing the formation of neutrophil extracellular traps through interacting with SYK after SAH. TREM1 may be a a promising therapeutic target for SAH.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 81%

Section: Introductionsupporting

confidence: 79%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TREM1 Regulates Neuroinflammatory Injury by Modulate Proinflammatory Subtype Transition of Microglia and Formation of Neutrophil Extracellular Traps via Interaction With SYK in Experimental Subarachnoid Hemorrhage

Zeng

et al. 2021

Front. Immunol.

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A Neutrophil Hijacking Nanoplatform Reprograming NETosis for Targeted Microglia Polarizing Mediated Ischemic Stroke Treatment

Yin,

Wang,

Pei

et al. 2024

Advanced Science

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Precise and efficient regulation of microglia is vital for ischemic stroke therapy and prognosis. The infiltration of neutrophils into the brain provides opportunities for regulatory drugs across the blood–brain barrier, while hindered by neutrophil extracellular traps (NETs) and targeted delivery of intracerebral drugs to microglia. This study reports an efficient neutrophil hijacking nanoplatform (referred to as APTS) for targeted A151 (a telomerase repeat sequence) delivery to microglia without the generation of NETs. In the middle cerebral artery occlusion (MCAO) mouse model, the delivery efficiency to ischemic stroke tissues increases by fourfold. APTS dramatically reduces the formation of NETs by 2.2‐fold via reprogramming NETosis to apoptosis in neutrophils via a reactive oxygen species scavenging‐mediated citrullinated histone 3 inhibition pathway. Noteworthy, A151 within neutrophils is repackaged into apoptotic bodies following the death pattern reprogramming, which, when engulfed by microglia, polarizes microglia to an anti‐inflammatory M2 phenotype. After four times treatment, the cerebral infarction area in the APTS group decreases by 5.1‐fold. Thus, APTS provides a feasible, efficient, and practical drug delivery approach for reshaping the immune microenvironment and treating brain disorders in the central nervous system.

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Building a better NET: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders

Ngo

Gollomp

2022

Research and Practice in Thrombosis and Haemostasis

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Infectious and inflammatory stimuli induce the release of neutrophil extracellular traps (NETs), webs of cell‐free (cf) DNA complexed with histones and antimicrobial proteins, that capture and kill pathogens. Despite their protective role in the initial stages of sepsis, excessive NET release accompanied by NET degradation, leads to the release of NET degradation products (NDPs), including cfDNA, histones, and myeloperoxidase that injure the microvasculature. Murine studies have shown that clearance or neutralization of NDPs improves outcomes, demonstrating that NETs have a causal link to disease and are not merely biomarkers. Recently, elevated NDPs have been associated with disease severity in sepsis and coronavirus disease 2019, raising further interest in targeting NETs. Many propose eliminating NETs, either by preventing their release, or by degrading them. However, NET inhibition may impede the innate immune response and is difficult to achieve in rapid‐onset conditions such as sepsis. On the other hand, approaches that accelerate NET degradation have met with mixed results in murine studies, raising the concern that this strategy may liberate NET‐captured pathogens while increasing circulating levels of harmful NDPs. Alternative NET‐directed strategies include therapies that neutralize, sequester, or remove NDPs from the circulation. Others propose modifying released NETs to decrease their capacity to induce collateral tissue damage while enhancing their ability to capture microorganisms. Synthetic NETs have also been designed to combat antibiotic‐resistant organisms. Although it is still in its infancy, the field of NET‐targeted therapeutics is advancing rapidly and may soon find application in the treatment of sepsis and other inflammatory disorders.

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Neutrophil Extracellular Traps may be a Potential Target for Treating Early Brain Injury in Subarachnoid Hemorrhage

Cited by 56 publications

References 60 publications

TREM1 Regulates Neuroinflammatory Injury by Modulate Proinflammatory Subtype Transition of Microglia and Formation of Neutrophil Extracellular Traps via Interaction With SYK in Experimental Subarachnoid Hemorrhage

TREM1 Regulates Neuroinflammatory Injury by Modulate Proinflammatory Subtype Transition of Microglia and Formation of Neutrophil Extracellular Traps via Interaction With SYK in Experimental Subarachnoid Hemorrhage

A Neutrophil Hijacking Nanoplatform Reprograming NETosis for Targeted Microglia Polarizing Mediated Ischemic Stroke Treatment

Building a better NET: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders

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