IL-33 Provides Neuroprotection through Suppressing Apoptotic, Autophagic and NF-κB-Mediated Inflammatory Pathways in a Rat Model of Recurrent Neonatal Seizure

Gao, Yuan; Luo, Chengliang; Li, Lili; Ye, Guanghua; Gao, Cheng; Wang, Hao‐Chen; Huang, Wenwen; Wang, Tao; Wang, Zufeng; Hóng, Ní; Chen, Xiping; Tao, Luyang

doi:10.3389/fnmol.2017.00423

Cited by 30 publications

(19 citation statements)

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“…IL-33 exerts protective and toxic bidirectional actions in many organs, depending on its doses. IL-33 induces microglia-mediated neuroinflammation also [11] , while it exhibits neuroprotection effects [ 12 , 13 ]. Moreover, IL-33 promotes microglial synapse engulfment and neural circuit development [14] .…”

Section: Introductionmentioning

confidence: 99%

IL-33 suppresses GSK-3β activation through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway

Nishizaki¹

2018

Heliyon

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AimsThe present study was conducted to explore the effect of interleukin-33 (IL-33) on glycogen synthase kinase-3β (GSK-3β) activation involving Tau phosphorylation, a critical causative factor for Alzheimer's disease (AD).Main methodsExperiments were performed using PC-12 cells. Target proteins were knocked-down by transfecting with the siRNA for each protein. The kinase activities were assessed by monitoring phosphorylation of Thr308 and Ser473 for Akt and phosphorylation of Ser9 and Tyr216 for GSK-3β in the Western blotting.Key findingsExogenously applied IL-33 activated Akt and inactivated GSK-3β. IL-33-induced Akt activation and GSK-3β inactivation were significantly inhibited by knocking-down myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6), receptor-interacting protein (RIP), or phosphatidylinositol 3 kinase (PI3K). IL-33 neutralized amyloid β1-42 (Aβ1-42)-induced Akt inactivation and GSK-3β activation.SignificanceThe results of the present study show that IL-33 inactivates GSK-3β through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway and inhibits Aβ1-42-induced GSK-3β activation. This suggests that IL-33 could restrain GSK-3β-mediated Tau phosphorylation in AD.

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Section: Introductionmentioning

confidence: 99%

IL-33 suppresses GSK-3β activation through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway

Nishizaki¹

2018

Heliyon

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“…Numerous literature identified that IL-33 was produced by endothelial cells and astrocytes but not by microglia or neurons, and its receptor, ST2, was mainly expressed in microglia and astrocytes cultured in vitro ( Huang et al, 2015 ). Other reports revealed that IL-33 and ST2 were mainly localized in astrocytes, microglia, and neurons, as well as oligodendrocytes after brain injury ( Jiang et al, 2012 ; Allan et al, 2016 ; Gao et al, 2017a ). Consistent with the latter, our current results showed that IL-33 was expressed at high levels in the Sham group and almost exclusively co-localized in the nucleus of oligodendrocytes, and the cytoplasm of neurons.…”

Section: Discussionmentioning

confidence: 89%

“…Noteworthily, less is known about the role and underlying mechanisms of IL-33 in the epilepsy model. Our previous studies suggested that IL-33 could exert a neuroprotective role by regulating the Bcl-2/CC-3 signaling pathway after RNS ( Gao et al, 2017a ). Consistent with previous studies, our current results revealed that IL-33 administration reduced the number of TUNEL-positive cells at 72 h post-RNS, suggesting that IL-33 processes the anti-apoptotic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Try to reduce the suffering and the number of animals used. The experimental procedure for establishing the RNS model had been described from our laboratory previously ( Molofsky et al, 2015 ; Gao et al, 2017a ). In Brief, on postnatal day (P7), SD rats ( n = 48) were divided randomly into five groups: Sham + PBS group, RNS + PBS, RNS + IL-33 group, RNS + Anti-IL-33 group and RNS + Anti-IL-33 + IL-33 group.…”

Section: Methodsmentioning

confidence: 99%

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IL-33 Alleviated Brain Damage via Anti-apoptosis, Endoplasmic Reticulum Stress, and Inflammation After Epilepsy

et al. 2020

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Interleukin (IL)-33 belongs to a novel chromatin-associated cytokine newly recognized by the IL-1 family, and its specific receptor is the orphan IL-1 receptor (ST2). Cumulative evidence suggests that IL-33 plays a crucial effect on the pathological changes and pathogenesis of central nervous system (CNS) diseases and injuries, such as recurrent neonatal seizures (RNS). However, the specific roles of IL-33 and its related molecular mechanisms in RNS remain confused. In the present study, we investigated the protein expression changes and co-localized cell types of IL-33 or ST2, as well as the effect of IL-33 on RNS-induced neurobehavioral defects, weight loss, and apoptosis. Moreover, an inhibitor of IL-33, anti-IL-33 was performed to further exploited underlying mechanisms. We found that administration of IL-33 up-regulated the expression levels of IL-33 and ST2, and increased the number of its co-localization with Olig-2-positive oligodendrocytes and NeuN-positive neurons at 72 h post-RNS. Noteworthily, RNS-induced neurobehavioral deficits, bodyweight loss, and spatial learning and memory impairment, as well as cell apoptosis, were reversed by IL-33 pretreatment. Additionally, the increase in IL-1β and TNF-α levels, up-regulation of ER stress, as well as a decrease in anti-apoptotic protein Bcl-2 and an increase in pro-apoptotic protein CC-3 induced by RNS are prevented by administration of IL-33. Moreover, IL-33 in combination with Anti-IL-33 significantly inverted the effects of IL-33 or Anti-IL-33 alone on apoptosis, ER stress, and inflammation. Collectively, these data suggest that IL-33 attenuates RNS-induced neurobehavioral disorders, bodyweight loss, and spatial learning and memory deficits, at least in part through mechanisms involved in inhibition of apoptosis, ER stress, and neuro-inflammation.

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“…5a and b ). Recently, IL-33 was recognized as an important protector of cell survival [ 56 – 58 ]. In addition, it has been reported that exogenous IL-33 exhibits immunoprotective role in polymicrobial sepsis in mice by preventing early loss of T and B lymphocytes [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

IL-33 receptor (ST2) deficiency downregulates myeloid precursors, inflammatory NK and dendritic cells in early phase of sepsis

et al. 2018

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BackgroundSepsis is a life-threatening disease mediated by profound disturbances in systemic inflammatory response to infection. IL-33 is multifunctional regulator of numerous aspects of innate and adaptive immune response. The aim of this article was to further evaluate the role of IL-33 receptor (ST2) in different pathways of innate immunity during early polymicrobial sepsis.MethodsPolymicrobial sepsis was induced using cecal ligation and puncture (CLP) model in ST2 deficient (ST2−/−) and wild type BALB/c mice. Peritoneal and spleen cells were isolated for further phenotyping. Apoptosis was determined by immunohistochemistry and flow cytometry.ResultsDeletion of ST2 leads to increased susceptibility to early manifestations of sepsis as evaluated by clinical signs and survival. These are accompanied by decrease in the total number of neutrophils, eosinophils and mast cells in peritoneal cavity 12 h after CLP. In early sepsis there was also low number of precursors of myeloid cells in particular CD11b+Ly6G+Ly6Clow cells in spleen of ST2−/− mice. Although the number of NK cells in the spleen was similar, there were significant differences in the presence of inflammatory IFN-γ and IL-17 producing NK cells. Further, ST2 deletion affects the phenotype and maturation of dendritic cell in sepsis. The total number of dendritic cells in the spleen was lower as well as IL-12 expressing dendritic cells. Finally, there was higher frequency of active caspase-3 positive and early apoptotic cells, in particular CD11c positive cells, in spleen of septic ST2−/− mice.ConclusionTaken together, our data provide the evidence that ST2 deficiency in early phase of sepsis downregulates myeloid precursors, inflammatory NK and dendritic cells.

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IL-33 Provides Neuroprotection through Suppressing Apoptotic, Autophagic and NF-κB-Mediated Inflammatory Pathways in a Rat Model of Recurrent Neonatal Seizure

Cited by 30 publications

References 51 publications

IL-33 suppresses GSK-3β activation through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway

IL-33 suppresses GSK-3β activation through an ST2-independent MyD88/TRAF6/RIP/PI3K/Akt pathway

IL-33 Alleviated Brain Damage via Anti-apoptosis, Endoplasmic Reticulum Stress, and Inflammation After Epilepsy

IL-33 receptor (ST2) deficiency downregulates myeloid precursors, inflammatory NK and dendritic cells in early phase of sepsis

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