Systemic inflammation after stroke: implications for post‐stroke comorbidities

EMBO Molecular Medicine, Journal Year: 2022, Volume and Issue: 14(9)

Published: Aug. 15, 2022

Language: Английский

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Inhibition of neutrophil extracellular trap formation ameliorates neuroinflammation and neuronal apoptosis via STING-dependent IRE1α/ASK1/JNK signaling pathway in mice with traumatic brain injury

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Sept. 30, 2023

Neuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout tissue TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, biological function underlying mechanisms NETs TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor to investigate role TBI.Controlled cortical impact model was performed establish TBI. 2'3'-cGAMP (an activator stimulating Interferon genes (STING)), C-176 (a STING inhibitor), Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] administrated explore mechanism by which promote neuroinflammation neuronal apoptosis Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil trap formation, overexpressed adenoviruses cortex mice 1 day before The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, quantitative-PCR this study.Neutrophils form presenting circulation at 3 days Cl-amidine treatment improved neurological functions, reduced cerebral lesion volume, edema, restored blood flow (CBF) In addition, exerted neuroprotective effects attenuating BBB disruption, inhibiting immune cell infiltration, alleviating death Moreover, inhibited microglia/macrophage pro-inflammatory polarization promoted anti-inflammatory Mechanistically, ligand abolished neuroprotection via IRE1α/ASK1/JNK signaling pathway Importantly, overexpression PAD4 promotes or IRE1α effectively neurodestructive TBI.Altogether, first demonstrate that inhibition ameliorated neuroinflammation, apoptosis, deficits STING-dependent Thus, may provide promising therapeutic approach early management

Language: Английский

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Neutrophils in Physiology and Pathology

Annual Review of Pathology Mechanisms of Disease, Journal Year: 2024, Volume and Issue: 19(1), P. 227 - 259

Published: Jan. 24, 2024

Infections, cardiovascular disease, and cancer are major causes of disease death worldwide. Neutrophils inescapably associated with each these health concerns, by either protecting from, instigating, or aggravating their impact on the host. However, disorders has a very different etiology, understanding how neutrophils contribute to them requires intricacies this immune cell type, including nonimmune contributions physiology pathology. Here, we review some intricacies, from basic concepts in neutrophil biology, such as production acquisition functional diversity, variety mechanisms which they preventing infections, events, cancer. We also poorly explored aspects promote favoring tissue repair discuss discoveries about biology inform development new therapeutic strategies.

Language: Английский

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HMGB1: A New Target for Ischemic Stroke and Hemorrhagic Transformation

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

Published: May 14, 2024

Abstract Stroke in China is distinguished by its high rates of morbidity, recurrence, disability, and mortality. The ultra-early administration rtPA essential for restoring perfusion acute ischemic stroke, though it concurrently elevates the risk hemorrhagic transformation. High-mobility group box 1 (HMGB1) emerges as a pivotal player neuroinflammation after brain ischemia ischemia–reperfusion. Released passively necrotic cells actively secreted, including direct secretion HMGB1 into extracellular space packaging intracellular vesicles immune cells, glial platelets, endothelial represents prototypical damage-associated molecular pattern (DAMP). It intricately involved pathogenesis atherosclerosis, thromboembolism, detrimental inflammation during early phases stroke. Moreover, significantly contributes to neurovascular remodeling functional recovery later stages. Significantly, mediates transformation facilitating neuroinflammation, directly compromising integrity blood–brain barrier, enhancing MMP9 through interaction with rtPA. As systemic inflammatory factor, also implicated post-stroke depression an elevated stroke-associated pneumonia. role extends influencing polarizing various subtypes cells. This includes mediating excitotoxicity due excitatory amino acids, autophagy, release, NET formation, autocrine trophic pathways. Given multifaceted role, recognized crucial therapeutic target prognostic marker stroke In this review, we summarize structure redox properties, pathways, regulation cell activity, pathophysiological mechanisms hemorrhage HMGB1, which will pave way developing new neuroprotective drugs, reduction expansion thrombolysis time window.

Language: Английский

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Platelets in the NETworks interweaving inflammation and thrombosis

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Aug. 1, 2022

Platelets are well characterized for their indispensable role in primary hemostasis to control hemorrhage. Research over the past years has provided a substantial body of evidence demonstrating that platelets also participate host innate immunity. The surface expression pattern recognition receptors, such as TLR2 and TLR4, provides with ability sense bacterial products environment. Platelet α-granules contain microbicidal proteins, chemokines growth factors, which upon release may directly engage pathogens and/or contribute inflammatory signaling. Additionally, platelet interactions neutrophils enhance neutrophil activation often crucial induce sufficient immune response. In particular, can activate form extracellular traps (NETs). This specific effector function is by expelling chromatin fibres decorated histones antimicrobial proteins into space where they serve trap kill pathogens. Until now, mechanisms signaling pathways between inducing NET formation still not fully characterized. NETs were detected thrombotic lesions several disease backgrounds, pointing towards an interface neutrophils, thrombosis, known immunothrombosis. negatively charged DNA within procoagulant surface, particular NET-derived platelets. light current COVID-19 pandemic, topic immunothrombosis become more relevant than ever, majority patients display thrombi lung capillaries other vascular beds. Furthermore, be found tissues associated increased mortality. Here, virus infiltration lead cytokine storm potently activates leads massive formation. resulting presumably coagulation further contributing subsequent emergence microthrombi pulmonary capillaries. this review, we will discuss interplay potential alliance influence course diseases. A better understanding underlying molecular identification treatment targets utmost importance increase patients' survival improve clinical outcome.

Language: Английский

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Pathophysiological mechanisms of thrombosis in acute and long COVID-19

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Nov. 16, 2022

COVID-19 patients have a high incidence of thrombosis, and thromboembolic complications are associated with severe mortality. disease is hyper-inflammatory response (cytokine storm) mediated by the immune system. However, role inflammatory in thrombosis remains incompletely understood. In this review, we investigate crosstalk between inflammation context COVID-19, focusing on contributions to pathogenesis propose combined use anti-inflammatory anticoagulant therapeutics. Under conditions, interactions neutrophils platelets, platelet activation, monocyte tissue factor expression, microparticle release, phosphatidylserine (PS) externalization as well complement activation collectively involved immune-thrombosis. Inflammation results apoptosis blood cells, leading release PS cells microparticles, which significantly enhances catalytic efficiency tenase prothrombinase complexes, promotes thrombin-mediated fibrin generation local clot formation. Given risk importance antithrombotic therapies has been generally recognized, but certain deficiencies treatment gaps remain. Antiplatelet drugs not combination treatments, thus fail dampen procoagulant activity. Current treatments also do an optimal time for anticoagulation. The efficacy depends therapy initiation. best early possible after diagnosis, ideally stage disease. We elaborate mechanisms long COVID complications, including persistent inflammation, endothelial injury dysfunction, coagulation abnormalities. above-mentioned contents provide therapeutic strategies further improve patient outcomes.

Language: Английский

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Smart Liposomal Nanocarrier Enhanced the Treatment of Ischemic Stroke through Neutrophil Extracellular Traps and Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway Inhibition of Ischemic Penumbra

ACS Nano, Journal Year: 2023, Volume and Issue: 17(18), P. 17845 - 17857

Published: Sept. 15, 2023

Brain inflammation is regarded as one of the leading causes that aggravates secondary brain injury and hinders prognosis ischemic stroke. After stroke, high quantities peripheral neutrophils are recruited to lesions release neutrophil extracellular traps (NETs), aggravation blood-brain barrier (BBB) damage, activation microglia, ultimate neuronal death. Herein, a smart multifunctional delivery system has been developed regulate immune disorders in brain. Briefly, Cl-amidine, an inhibitor peptidylarginine deiminase 4 (PAD4), encapsulated into self-assembled liposomal nanocarriers (C-Lipo/CA) modified by reactive oxygen species (ROS)-responsive polymers fibrin-binding peptide achieve targeting stimuli-responsive drug. In mouse model cerebral artery occlusion/reperfusion (MCAO), C-Lipo/CA can suppress NETs process (NETosis) further inhibit cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator interferon genes (cGAS-STING) pathway addition, MCAO mice treated with significantly mitigated reperfusion injury, reduction area infarction 12.1%, compared saline group about 46.7%. These results demonstrated C-Lipo/CA, which integrated microglia regulation, BBB protection, neuron survival, exerts potential therapy strategy maximize ameliorating mortality

Language: Английский

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Ischemic Stroke and SARS-CoV-2 Infection: The Bidirectional Pathology and Risk Morbidities

Neurology International, Journal Year: 2022, Volume and Issue: 14(2), P. 391 - 405

Published: April 24, 2022

Stroke is a fatal morbidity that needs emergency medical admission and immediate attention. COVID-19 ischemic brain damage closely associated with common neurological symptoms, which are extremely difficult to treat medically, risk factors. We performed literature research about ischemia in

Language: Английский

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The relationship between systemic inflammation index, systemic immune-inflammatory index, and inflammatory prognostic index and 90-day outcomes in acute ischemic stroke patients treated with intravenous thrombolysis

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Sept. 30, 2023

To explore the association of systemic inflammatory index (SIRI), immune-inflammatory (SII) and prognosis (IPI) with 90d outcomes in patients acute ischemic stroke (AIS) after intravenous thrombolysis.The who underwent thrombolysis were enrolled present study from September 2019 to December 2022. According relevant blood indexes obtained 24 h admission, corresponding values SIRI, SII IPI calculated. The correlation among SII, IPI, admission NIHSS scores was examined by Spearman analysis. ROC curve analysis conducted determine optimal cut-off value their sensitivity specificity evaluate predictive on for poor prognosis. investigate whether high independent predictors within 90 days, variables P-value < 0.05 during univariate included multivariate analysis.Compared good outcome group, group had higher SII. showed that levels significantly correlated score (r = 0.338, 0.356, 0.427, respectively; Ps 0.001). Univariate Multivariate logistic regression revealed as risk factors 90-day (OR 1.09, 1.003 7.109, respectively).High are AIS undergoing thrombolysis.

Language: Английский

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NETosis induction reflects COVID-19 severity and long COVID: insights from a 2-center patient cohort study in Israel

Journal of Thrombosis and Haemostasis, Journal Year: 2023, Volume and Issue: 21(9), P. 2569 - 2584

Published: April 11, 2023

COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing morbidity mortality.This study evaluated immunothrombosis markers a comprehensive cohort of recovered patients, including the association NETs with long COVID.One-hundred-seventy-seven patients were recruited from clinical cohorts at 2 Israeli centers: (mild/moderate, severe/critical), convalescent (recovered COVID), along 54 non-COVID controls. Plasma was examined for platelet activation, coagulation, NETs. Ex vivo NETosis induction capability after neutrophil incubation patient plasma.Soluble P-selectin, factor VIII, von Willebrand factor, 4 significantly elevated versus Myeloperoxidase (MPO)-DNA complex levels increased only severe did not differentiate between severities or correlate thrombotic markers. strongly correlated illness severity/duration, activation markers, coagulation factors, reduced upon dexamethasone treatment recovery. Patients COVID maintained higher induction, but NET fragments, compared patients.Increased can detected COVID. appears more sensitive measurement than MPO-DNA differentiating disease Ongoing may provide insights into pathogenesis serve as surrogate marker persistent pathology. This emphasizes need explore neutrophil-targeted therapies chronic COVID-19.

Language: Английский

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