NLRP3 inflammasome-mediated microglial pyroptosis is critically involved in the development of post-cardiac arrest brain injury

Chang, Yuan; Zhu, Jing; Wang, Di; Li, Hua; He, Yihua; Liu, Kewei; Wang, Xiaoqiang; Peng, Yuqin; Pan, Suyue; Huang, Kaibin

doi:10.1186/s12974-020-01879-1

Cited by 65 publications

(78 citation statements)

References 51 publications

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“…Reports in scientific literature suggest that the NLRP3 inflammasome may be contributing to the release of cytokines such as IL-1 in SARS-CoV-2-induced hyperinflammation [43][44][45]. In the microglia, activation of NLRP3 by extracellular ATP, certain bacterial toxins, crystalline and particulate matters results in caspase-1 activation which then cleaves the precursors of IL-1β and IL-18 to generate active IL-1β and IL-18, resulting in neuroinflammation and pyroptosis [46][47][48]. In this study, we showed that in addition to increasing IL-1β production, SARS-CoV-2 spike S1 protein activated NLRP3 inflammasome and increased caspase-1 activity in BV-2 microglia.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

Olajide

Iwuanyanwu

Adegbola

2020

Preprint

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The emergence of SARS‐CoV‐2 has resulted in a global pandemic. In addition to respiratory complications as a result of SARS‐CoV‐2 illness, accumulating evidence suggests that neurological and neuropsychiatric symptoms are associated with the disease caused by the virus. In this study, we investigated the effects of the SARS‐CoV‐2 spike glycoprotein S1 stimulation on neuroinflammation in BV-2 microglia. Analyses of culture supernatants revealed an increase in the production of TNFα, IL-6, IL-1β and iNOS/NO. SARS‐CoV‐2 spike glycoprotein S1 increased protein expressions of phospho-p65 and phospho-IκB, as well as enhancing DNA binding and transcriptional activity of NF-κB. Pro-inflammatory effects of the glycoprotein effects were reduced in the presence of BAY11-7082 (1 μM). The presence of SARS‐CoV‐2 spike glycoprotein S1 in BV-2 microglia increased the protein expression of NLRP3, as well as caspase-1 activity. However, pre-treatment with CRID3 (1 μM) or BAY11-7082 (1 μM) resulted in the inhibition of NLRP3 inflammasome/caspase-1. It was also observed that CRID3 attenuated SARS‐CoV‐2 spike glycoprotein S1-induced increase in IL-1β production. Increased protein expression of p38 MAPK was observed in BV-2 microglia stimulated with the spike glycoprotein S1, and was reduced in the presence of SKF 86002. These results have provided the first evidence demonstrating SARS-CoV-2 spike S1 glycoprotein-induced neuroinflammation in BV-2 microglia. We propose that promotion of neuroinflammation by this glycoprotein is mediated through activation of NF-κB, NLRP3 inflammasome and p38 MAPK. These results are significant because of their relevance to our understanding of neurological and neuropsychiatric symptoms observed in patients infected with SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

Olajide

Iwuanyanwu

Adegbola

2020

Preprint

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“…Importantly, GSDMs have been verified as critical molecules of the pyroptosis program ( Wang et al, 2017 , 2018b ; Panganiban et al, 2018 ). Pyroptosis is a proinflammatory type of programmed cell death that frequently occurs upon microbial infection or other stimuli ( Chang et al, 2020 ). Pyroptosis serves a vital role in the clearance of pathogenic infection and removal of endogenous danger signals by destroying the protective niche for pathogens and inducing immune responses ( Kayagaki et al, 2011 ; Case et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Biological Functions of Gasdermins in Cancer: From Molecular Mechanisms to Therapeutic Potential

Wang

Chen

Zhang

2021

Front. Cell Dev. Biol.

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Pyroptosis is a type of lytic programmed cell death triggered by various inflammasomes that sense danger signals. Pyroptosis has recently attracted great attention owing to its contributory role in cancer. Pyroptosis plays an important role in cancer progression by inducing cancer cell death or eliciting anticancer immunity. The participation of gasdermins (GSDMs) in pyroptosis is a noteworthy recent discovery. GSDMs have emerged as a group of pore-forming proteins that serve important roles in innate immunity and are composed of GSDMA-E and Pejvakin (PJVK) in human. The N-terminal domains of GSDMs, expect PJVK, can form pores on the cell membrane and function as effector proteins of pyroptosis. Remarkably, it has been found that GSDMs are abnormally expressed in several forms of cancers. Moreover, GSDMs are involved in cancer cell growth, invasion, metastasis and chemoresistance. Additionally, increasing evidence has indicated an association between GSDMs and clinicopathological features in cancer patients. These findings suggest the feasibility of using GSDMs as prospective biomarkers for cancer diagnosis, therapeutic intervention and prognosis. Here, we review the progress in unveiling the characteristics and biological functions of GSDMs. We also focus on the implication and molecular mechanisms of GSDMs in cancer pathogenesis. Investigating the relationship between GSDMs and cancer biology could assist us to explore new therapeutic avenues for cancer prevention and treatment.

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“…Ischemic (27)(28)(29) or hemorrhagic stroke (20) can induce apoptotic and pyroptotic microglial cell death. Suppressing microglial pyroptosis alleviates brain-blood barrier disruption and neuronal injury after subarachnoid hemorrhage (30), and improves survival and neurological outcomes after cardiac arrest (31).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-preconditioned mesenchymal stem cells attenuate microglial pyroptosis after intracerebral hemorrhage

Liu¹,

He²,

Huang³

et al. 2021

Ann Transl Med

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Background: Microglia plays a vital role in neuroinflammation, contributing to the pathogenesis of intracerebral hemorrhage (ICH)-induced brain injury. Mesenchymal stem cells (MSCs) hold great potential for treating ICH. We previously revealed that MSCs ameliorate the microglial pyroptosis caused by an ischemic stroke. However, whether MSCs can modulate microglial pyroptosis after ICH remains unknown.This study aimed to investigate the neuroprotective effects of hypoxia-preconditioned olfactory mucosa MSCs (OM-MSCs) on ICH and the possible mechanisms.Methods: ICH was induced in mice via administration of collagenase IV. At 6 h post-ICH, 2-4×10 5 normoxic/hypoxic OM-MSCs or saline were intracerebrally administered. To evaluate the neuroprotective effects, the behavioral outcome, apoptosis, and neuronal injury were measured. Microglia activation and proinflammatory cytokines were applied to detect neuroinflammation. Microglial pyroptosis was determined by western blotting, immunofluorescence staining, and transmission electron microscopy (TEM). Results:The two OM-MSC-transplanted groups exhibited significantly improved functional recovery and reduced neuronal injury, especially the hypoxic OM-MSCs group. Hypoxic OM-MSCs attenuated microglial activation as well as the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Moreover, we found that hypoxia-preconditioned OM-MSCs ameliorated pyroptosis by diminishing the levels of pyroptosis-associated proteins in peri-hematoma brain tissues, decreasing the expression of the microglial nod-like receptor family protein 3 (NLRP3) and caspase-1, and reducing the membrane pores on microglia post-ICH.Conclusions: Our study showed that hypoxic preconditioning augments the therapeutic efficacy of OM-MSCs, and hypoxia-preconditioned OM-MSCs alleviate microglial pyroptosis in the ICH model.

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NLRP3 inflammasome-mediated microglial pyroptosis is critically involved in the development of post-cardiac arrest brain injury

Cited by 65 publications

References 51 publications

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

SARS-CoV-2 spike glycoprotein S1 induces neuroinflammation in BV-2 microglia

Biological Functions of Gasdermins in Cancer: From Molecular Mechanisms to Therapeutic Potential

Hypoxia-preconditioned mesenchymal stem cells attenuate microglial pyroptosis after intracerebral hemorrhage

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