Neutrophil extracellular traps promote immune escape in hepatocellular carcinoma by up-regulating CD73 through Notch2

Cancer Letters, Journal Year: 2024, Volume and Issue: 598, P. 217098 - 217098

Published: July 4, 2024

Immune escape is the main reason that immunotherapy ineffective in hepatocellular carcinoma (HCC). Here, this study illustrates a pathway mediated by neutrophil extracellular traps (NETs) can promote immune of HCC. Mechanistically, we demonstrated NETs up-regulated CD73 expression through activating Notch2 nuclear factor kappa B (NF-κB) pathway, promoting regulatory T cells (Tregs) infiltration to mediate In addition, found similar results mouse HCC models hydrodynamic plasmid transfection. The treatment deoxyribonuclease I (DNase I) could inhibit action and improve therapeutic effect anti-programmed cell death protein 1 (PD-1). summary, our revealed targeting was promising anti-PD-1.

Language: Английский

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Skull bone marrow and skull meninges channels: redefining the landscape of central nervous system immune surveillance

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 28, 2025

Abstract The understanding of neuroimmune function has evolved from concepts immune privilege and protection to a new stage interaction. discovery skull meninges channels (SMCs) opened avenues for central nervous system (CNS) immunity. Here, we characterize bone marrow SMCs by detailing the anatomical structures adjacent skull, differences between peripheral marrow, mainstream animal processing methods, role in monitoring various CNS diseases. Additionally, highlight several unresolved issues based on current research findings, aiming guide future directions.

Language: Английский

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TRIM21 knockdown alleviates hemorrhage induced hepatic ischemia reperfusion injury by suppressing ferroptosis-induced NETs

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: May 14, 2025

Language: Английский

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Spatiotemporal dynamic changes of meningeal microenvironment influence meningeal lymphatic function following subarachnoid hemorrhage: from inflammatory response to tissue remodeling

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: May 16, 2025

Meningeal lymphatic vessels (mLVs) play a critical role in clearing erythrocytes from the subarachnoid space and immune cells brain parenchyma following hemorrhage (SAH). However, drainage function of mLVs is impaired during acute stage after SAH gradually recovers subacute phase. We aimed to investigate meningeal transcriptional response post-SAH elucidate dynamic influence microenvironment on function. employed bioinformatics analysis single-cell RNA sequencing spatial transcriptomics characterize spatiotemporal changes early post-SAH. In mouse model SAH, potential growth factor that promoted repair were further investigated validated. During phase, myeloid infiltrated meninges triggered inflammatory responses. fibroblast population expanded significantly, contributing tissue remodeling. The interplay between fibroblasts regulated cell migration phenotypic transition, potentially affecting mLVs. Notably, placental (PGF) emerged as most prominent ligand within VEGF signaling pathway received by endothelial (mLECs) This event was associated with recovery Our study revealed transformation an "inflammatory response" phase "tissue remodeling" SAH. Monocyte-derived macrophages self-recruiting neutrophils contributed impairment stage, while PGF might serve key promoting response. These findings provided novel insights into cellular dynamics underlying dysfunction

Language: Английский

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Neutrophil Extracellular Traps Induce Brain Edema Around Intracerebral Hematoma via ERK-Mediated Regulation of MMP9 and AQP4

Translational Stroke Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

Perihematomal edema (PHE) significantly aggravates secondary brain injury in patients with intracerebral hemorrhage (ICH), yet its detailed mechanisms remain elusive. Neutrophil extracellular traps (NETs) are known to exacerbate neurological deficits and worsen outcomes after stroke. This study explores the potential role of NETs pathogenesis following ICH. The rat ICH model was created, immunofluorescence Western blot were used examine neutrophil accumulation, NET markers citrullinated histone H3 (CitH3) myeloperoxidase (MPO), tight junction proteins (ZO-1 Occludin), Aquaporin-4 (AQP4), matrix metalloproteinase-9 (MMP-9), ERK phosphorylation (p-ERK) tissues surrounding hematoma. TUNEL staining behavioral tests employed evaluate neuronal apoptosis dysfunction, while blood-brain barrier (BBB) permeability also measured by Evans blue water content. Furthermore, molecular related NETs-induced PHE investigated using NETs, ERK, MMP-9 AQP4 regulators, respectively. Ly6G+ neutrophils hematoma developed within 3 days post-ICH. decreased proteins, destroyed BBB integrity, promoted edema, increased apoptosis, exacerbated deficits. Conversely, inhibition mitigated PHE, reduced improved functions. Mechanistically, NET-induced originated from impairment via ERK/MMP9 pathway, coupled ERK-mediated downregulation perihematomal regions. These findings elucidated effects on which offered promising insights for targeting relieve

Language: Английский

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Perivascular Neutrophil Extracellular Traps Exacerbate Microvasospasm After Experimental Subarachnoid Hemorrhage

Stroke, Journal Year: 2024, Volume and Issue: 55(12), P. 2872 - 2881

Published: Oct. 30, 2024

BACKGROUND: Subarachnoid hemorrhage (SAH) can lead to acute or delayed cerebral ischemia. Recent findings have revealed that spasm of microvessels, called microvasospasm, may contribute SAH-related ischemia, and perivascular inflammation is considered important in the development microvasospasms. However, owing difficulty investigating dynamics vascular events, little known about mechanisms underlying METHODS: We established an experimental system aiming investigate pathology SAH by combining a mouse model with intravital 2-photon imaging. was induced intracisternal blood injection, distribution erythrocytes, neutrophil behavior, morphological changes pial arterioles were analyzed over time microscopy To further explore role neutrophils extracellular traps (NETs) we performed depletion intraperitoneal administration neutrophil-specific antibody NETs removal DNase. RESULTS: Erythrocytes immediately distributed space after induction; intensively infiltrated within 2 days subsequently showed NETosis; same region developed pearl-string-like microvasospasms subacute phase. Neutrophil significantly reduced number Furthermore, drastically CONCLUSIONS: By establishing unique system, demonstrated could be new therapeutic target for

Language: Английский

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Reimagining the meninges from a neuroimmune perspective: a boundary, but not peripheral

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Nov. 15, 2024

Recent advances in neuroscience have transformed our understanding of the meninges, layers surrounding central nervous system (CNS). Two key findings advanced understanding: researchers identified cranial bone marrow as a reservoir for meningeal immune cells, and rediscovered brain lymphatic system. Once viewed merely protective barrier, meninges are now recognized dynamic interface crucial neuroimmune interactions. This shift perspective highlights their unique role maintaining CNS balance, shaping development, regulating responses to injury disease. review synthesizes latest insights into anatomy function, with focus on newly structures such dural-associated lymphoid tissues (DALT) arachnoid cuff exit (ACE) points. We also examine diverse cell populations within interactions CNS, underscoring emerging view active participants immunity. Finally, we outline critical unanswered questions about immunity, proposing directions future research. By addressing these knowledge gaps, aim deepen meninges' health disease, potentially paving way novel therapeutic approaches.

Language: Английский

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Neutrophils Extracellular Traps Myeloperoxidase and Elastase Predict Cerebral Vasospasms after Aneurysmal Subarachnoid Hemorrhage

Heliyon, Journal Year: 2024, Volume and Issue: 10(23), P. e40562 - e40562

Published: Nov. 20, 2024

Aneurysmal subarachnoid hemorrhage (aSAH) is a highly fatal and morbid disease. Despite successful coiling or clipping of ruptured aneurysm, the patients suffer post-aSAH complications, including early brain injury, cerebral vasospasm (CVS), delayed ischemia (DCI), systemic infections that mainly determine clinical outcomes. Diagnostic biomarkers to predict accurately complications are needed. In this prospective exploratory study, we investigated predictive value neutrophil extracellular traps (NETs) components for CVS after aSAH. 62 with aSAH, 17 unruptured aneurysms, 12 healthy controls were included. The serum levels myeloperoxidase (MPO), elastase (ELA), citrullinated histone H3 (cH3) on day 1 4 hospital admission measured ELISA. Data scaled using Yeo-Johnson transformation. Values in two groups compared t-test multiple ANOVA. Logistic regression was used model outcome probability, CVS, as function ELISA values. Among those who suffered aSAH had significantly higher MPO (113.9 ± 294.4 vs. 422.3 319.0 ng/ml, p < 0.05), ELA (84.8 221.0 199.2 218.9 cH3 (0.0 0.0 2.8 1.5, 0.05) one suggesting involvement NETs pathophysiology events following Individually, taken SAH did not differ between without CVS. However, when together into logistic model, they allowed predicting high sensitivity (91 %) specificity (79 %). ELA, along other parameters, can be predictors serve guidance during treatment decisions management

Language: Английский

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12/15-Lipooxygenase Inhibition Reduces Microvessel Constriction and Microthrombi After Subarachnoid Hemorrhage in Mice

Translational Stroke Research, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

Language: Английский

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Intra-arterial Deoxyribonuclease therapy improves stroke outcomes in aged mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 29, 2024

Abstract Background Futile recanalization affects more than half of acute ischemic stroke (AIS) patients. Neutrophil extracellular traps (NETs) are a major factor microvascular hypoperfusion after stroke. Deoxyribonuclease I (DNase) targeting NETs exhibited neuroprotective effect in young mice with AIS. This study explored novel direct intra-arterial administration DNase therapy and its aged Method AIS was induced C57BL/6 followed by reperfusion immediate, via the internal carotid artery. Cerebral blood flow, neurological function, cerebral infarct volume, NET markers were examined. Results Direct significantly increased reduced deficit scores, latency to fall wire hang test, decreased neutrophil count both parenchyma micro vessels compared age-matched, vehicle controls. Conclusion Our data is first demonstrate that successful, provides efficient better outcomes during treatment large vessel occlusion mice. evidence for potential clinical application catheter delivered post-recanalization.

Language: Английский

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