Dataset Information

Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke.

ABSTRACT: BACKGROUND:Ischemic stroke is a leading cause of disability worldwide and characteristically accompanied by downregulation of the Wnt/?-catenin signaling. Activation of Wnt/?-catenin signaling emerges to attenuate neuroinflammation after ischemic stroke; however, its effect on modulating microglial polarization is largely unknown. Here, we explored whether Wnt/?-catenin pathway activator TWS119 facilitated long-term neurological recovery via modulating microglia polarization after experimental stroke. METHODS:Ischemic stroke mice model was induced by permanent distal middle cerebral artery occlusion plus 1?h hypoxia. TWS119 was administrated from day 1 to 14 after stroke. Neurological deficits were monitored up to 21?days after stroke. Angiogenesis, neural plasticity, microglial polarization, and microglia-associated inflammatory cytokines were detected in the peri-infarct cortex at days 14 and 21 after stroke. Primary microglia and mouse brain microvascular endothelial cell lines were employed to explore the underlying mechanism in vitro. RESULTS:TWS119 mitigated neurological deficits at days 14 and 21 after experimental stroke, paralleled by acceleration on angiogenesis and neural plasticity in the peri-infarct cortex. Mechanistically, cerebral ischemia induced production of microglia-associated proinflammatory cytokines and priming of activated microglia toward pro-inflammatory polarization, whereas TWS119 ameliorated microglia-mediated neuroinflammatory status following ischemic stroke and promoted angiogenesis by modulating microglia to anti-inflammatory phenotype. The beneficial efficacy of TWS119 in microglial polarization was largely reversed by selective Wnt/?-catenin pathway blockade in vitro, suggesting that TWS119-enabled pro-inflammatory to anti-inflammatory phenotype switch of microglia was possibly mediated by Wnt/?-catenin signaling. CONCLUSIONS:Wnt/?-catenin pathway activator TWS119 ameliorated neuroinflammatory microenvironment following chronic cerebral ischemia via modulating microglia towards anti-inflammatory phenotype, and facilitates neurological recovery in an anti-inflammatory phenotype polarization-dependent manner. Activation of Wnt/?-catenin pathway following ischemic stroke might be a potential restorative strategy targeting microglia-mediated neuroinflammation.

SUBMITTER: Song D

PROVIDER: S-EPMC6896312 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke.

Song Degang D Zhang Xiangjian X Chen Junmin J Liu Xiaoxia X Xue Jing J Zhang Lan L Lan Xifa X

Journal of neuroinflammation 20191206 1

<h4>Background</h4>Ischemic stroke is a leading cause of disability worldwide and characteristically accompanied by downregulation of the Wnt/β-catenin signaling. Activation of Wnt/β-catenin signaling emerges to attenuate neuroinflammation after ischemic stroke; however, its effect on modulating microglial polarization is largely unknown. Here, we explored whether Wnt/β-catenin pathway activator TWS119 facilitated long-term neurological recovery via modulating microglia polarization after experi ...[more]

PMID: 31810470

Similar Datasets

Project description:Early prediction of the potential for neurological recovery after resuscitation from cardiac arrest is difficult but important. Currently, no clinical finding or combination of findings are sufficient to accurately predict or preclude favorable recovery of comatose patients in the first 24 to 48 hours after resuscitation. Thus, life-sustaining therapy is often continued for several days in patients whose irrecoverable injury is not yet recognized. Conversely, early withdrawal of life-sustaining therapy increases mortality among patients who otherwise might have gone on to recover. In this work, we present Canonical Autocorrelation Analysis (CAA) and Canonical Autocorrelation Embeddings (CAE), novel methods suitable for identifying complex patterns in high-resolution multivariate data often collected in highly monitored clinical environments such as intensive care units. CAE embeds sets of datapoints onto a space that characterizes their latent correlation structures and allows direct comparison of these structures through the use of a distance metric. The methodology may be particularly suitable when the unit of analysis is not just an individual datapoint but a dataset, as for instance in patients for whom physiological measures are recorded over time, and where changes of correlation patterns in these datasets are informative for the task at hand. We present a proof of concept to illustrate the potential utility of CAE by applying it to characterize electroencephalographic recordings from 80 comatose survivors of cardiac arrest, aiming to identify patients who will survive to hospital discharge with favorable functional recovery. Our results show that with very low probability of making a Type 1 error, we are able to identify 32.5% of patients who are likely to have a good neurological outcome, some of whom have otherwise unfavorable clinical characteristics. Importantly, some of these had 5% predicted chance of favorable recovery based on initial illness severity measures alone. Providing this information to support clinical decision-making could motivate the continuation of life-sustaining therapies for these patients.

Project description:BackgroundIschemic stroke is the main cause of disability worldwide, leading to a serious socioeconomic burden. Ferroptosis is a non-apoptotic form of programmed cell death and is related to various diseases. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is considered a target of ferroptosis, but its specific role in ischemic stroke remains unclear. In this study, we investigate whether the inhibition of ACSL4 promotes the recovery of neurological function in a way that prevents ferroptosis.MethodsA transient cerebral ischemia model was established for mice by middle cerebral artery occlusion (MCAO); glutathione peroxidase 4 (GPx4), ACSL4 and cyclooxygenase 2 (COX2) were detected by Western blot, and changes to mitochondria were observed by a transmission electron microscope. A kit was used to determine iron levels and lipid peroxide indicators, such as glutathione peroxidase (GPx), reduced glutathione (GSH), total glutathione/oxidized glutathione (GSH/GSSG), lipid peroxidation, reactive oxygen species, superoxide and malonaldehyde. Following MCAO, a ferroptosis inhibitor, liproxstatin-1, was administered intranasally immediately at a concentration of 10 mg/kg. Rosiglitazone was used to inhibit ACSL4 and was administered intravenously 1 h before MCAO at a concentration of 0.4 mg/kg. Brain injury was determined by neurological deficit scores, neuroscore (28-point), corner test and gait analyses, at 24 and 72 h after stroke. Brain infarct volume was determined by 2, 3, 5-Triphenyltetrazolium chloride (TTC) staining at 72 h after stroke.ResultsAfter MCAO, GPx4 protein expression decreased, ACSL4 and COX2 protein expression increased, GPx activity decreased and iron accumulation. Transmission electron microscopy confirmed that the outer mitochondrial membrane of neurons had ruptured and mitochondrial cristae had decreased or disappeared. Liproxstatin-1 could significantly attenuate the decrease of GPx4 and the increase of COX2 after MCAO, dramatically reducing iron accumulation and decreasing GPx activity, accompanied by a marked reduction in changes in lipid peroxidation indicators. The use of rosiglitazone to inhibit ACSL4 could significantly improve neurological function and reduce the brain infarct volume at 72 h after stroke. Importantly, inhibiting ACSL4 could significantly attenuate the decline of GPx4 after MCAO and markedly attenuate iron accumulation and a decrease in GPx activity. Additionally, changes in lipid peroxidation indicators were also significantly inhibited.ConclusionThis study indicates that inhibiting ACSL4 can promote the recovery of neurological function after stroke by suppression of ferroptosis.

Dataset Information

Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke.

Publications

Wnt canonical pathway activator TWS119 drives microglial anti-inflammatory activation and facilitates neurological recovery following experimental stroke.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure