mTORC1 pathway disruption ameliorates brain inflammation following stroke
            <i>via</i>
            a shift in microglia phenotype from M1 type to M2 type

Li, Daojing; Wang, Chunjiong; Yao, Yang; Chen, Li; Liu, Guiyou; Zhang, Rongxin; Liu, Qiang; Shi, Fu‐Dong; Hao, Junwei

doi:10.1096/fj.201600495r

Cited by 120 publications

(79 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, rapamycin has anti‐inflammatory effects. Rapamycin apparently attenuates behavioral deficits after MCAO by shifting the microglia phenotype from M1 type to M2 type 36. It can attenuate secondary injury after focal ischemia by enhancing anti‐inflammatory activity of Tregs to restrain neuroinflammation 4.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Zhang

Kai

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveWhether activation or inhibition of the mTOR pathway is beneficial to ischemic injury remains controversial. It may result from the different reaction of ischemic penumbra and core to modulation of mTOR pathway after cerebral ischemia–reperfusion injury in rats.MethodsLonga's middle cerebral artery occlusion (MCAO) method was conducted to induce the focal cerebral ischemia–reperfusion. Western blot analysis was used to examine the protein expression involving mTOR pathway, apoptosis, and autophagy‐related proteins. TTC staining and Fluoro‐Jade B staining was conducted to detect the infarct volume and cell apoptosis, respectively. Neurological function was measured by modified neurological severity score and left‐biased swing.Results mTOR signaling pathway was activated in ischemic penumbra and decreased in ischemic core after ischemia and ischemia–reperfusion. Ischemia–reperfusion injury induced the increase in cleaved caspase 9 and caspase 3 both in ischemic penumbra and in ischemic core, whereas the expression of phosphorylated ULK1, Beclin 1 and LC3‐II was decreased. Rapamycin pre or postadministration inhibited the overactivation of mTOR pathway in ischemic penumbra. Ameliorated neurological function and reduced infarct volume were observed after pre or postrapamycin treatment. Rapamycin markedly decreased the number of FJB‐positive cells and the expression of cleaved caspase‐3 and cleaved caspase‐9 proteins as well as increased the activation of autophagy reflected by ULK1, Beclin‐1 and LC3.Interpretation mTOR signaling pathway was activated in ischemic penumbra after cerebral ischemia–reperfusion injury in rats. mTOR inhibitor rapamycin significantly decreased the mTOR activation and infarct volume and subsequently improved neurological function. These results may relate to inhibition of neuron apoptosis and activation of autophagy.

show abstract

Section: Discussionmentioning

confidence: 99%

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Zhang

Kai

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…Moreover, the interaction between microglia and other immune cells results in secondary inflammatory responses. Recent findings have involved microglia activation in the initiation and maintenance of inflammatory responses in the context of infectious brain diseases, acute CNS injury and several neurodegenerative diseases (Aoki et al, 2009; Fellner et al, 2013; Elmore et al, 2014; Liu et al, 2015; Kumar et al, 2016; Li D. et al, 2016; Xian et al, 2016). …”

Section: Microglia and Astrocytes In Neuroinflammationmentioning

confidence: 99%

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Song

Pei

Yao

et al. 2017

Front. Cell. Neurosci.

335

246

View full text Add to dashboard Cite

Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.

show abstract

“…Mammalian target of rapamycin (mTOR) pathway is a known regulator of immune responses, and inhibition of the mTORC1 pathway pharmacologically or genetically prevents microglial polarization toward the M1 pro-inflammatory phenotype in the context of ischemic stroke (Li et al, 2016; Xie et al, 2014). This is associated with reduced secondary damage and improved motor function.…”

Section: Recently Identified Molecular/cellular Targets and Approachesmentioning

confidence: 99%

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Shekhar

Cunningham

Pabbidi

et al. 2018

European Journal of Pharmacology

View full text Add to dashboard Cite

Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.

show abstract

mTORC1 pathway disruption ameliorates brain inflammation following stroke via a shift in microglia phenotype from M1 type to M2 type

Cited by 120 publications

References 42 publications

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Contact Info

Product

Resources

About