Recombinant adenovirus encoding NLRP3 RNAi attenuate inflammation and brain injury after intracerebral hemorrhage

Yuan, Bangqing; Shen, Haikang; Lin, Li; Su, Tonggang; Zhong, Shanchuan; Yang, Zhao

doi:10.1016/j.jneuroim.2015.08.002

Cited by 41 publications

(33 citation statements)

References 27 publications

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“…Activation of NLRP3 inflammasome and induction of its components aggravated the early brain injury after ICH, and blockades were protective reported by our [17] and other studies [8, 16]. In addition, a recent study showed that Nrf2 negatively regulates NLRP3 inflammasome activity by inhibiting ROS [18].…”

Section: Resultssupporting

confidence: 59%

“…The NLRP3 inflammasome, a best characterized pattern recognition receptor (PRR) in innate immune response, played a crucial component in the early brain injury post ICH [8, 16, 17] and was composed by a sensor (NLRP3 protein), an adaptor (ASC protein), and an effector (zymogen pro-caspase-1) [60, 61]. Production of ROS, mitochondrial DNA or the mitochondrial phospholipid cardiolipin, potassium efflux, changes in cell volume, calcium, and lysosomal impairments have all been proposed as critical active signals to trigger the activation of NLRP3 inflammasome [60, 61].…”

Section: Discussionmentioning

confidence: 99%

“…The NLRP3 (NALP3, cryopyrin) inflammasome [NLR (Nod-like receptor) family, pyrin domain-containing 3 inflammasome], a best characterized member of NLR family and one of the key components of innate immune system, has been reported by others [8, 16] and us [17] to take part in the processes of early brain injury after ICH via facilitating caspase-1 and interleukin-1beta (IL-1β) processing, which amplifies the inflammatory response and blockade or knockdown of NLRP3 inflammasome can alleviate the brain damages [8, 16, 17]. Recently, reports have indicated that Nrf2 could negatively regulate NLRP3 inflammasome activity by inhibiting reactive oxygen species (ROS)-induced NLRP3 inflammasome activation [18, 19].…”

Section: Introductionmentioning

confidence: 99%

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Isoliquiritigenin alleviates early brain injury after experimental intracerebral hemorrhage via suppressing ROS- and/or NF-κB-mediated NLRP3 inflammasome activation by promoting Nrf2 antioxidant pathway

Zeng

Chen

Ding

et al. 2017

J Neuroinflammation

292

214

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BackgroundIntracerebral hemorrhage (ICH) induces potently oxidative stress responses and inflammatory processes. Isoliquiritigenin (ILG) is a flavonoid with a chalcone structure and can activate nuclear factor erythroid-2 related factor 2 (Nrf2)-mediated antioxidant system, negatively regulate nuclear factor-κB (NF-κB) and nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathways, but its role and potential molecular mechanisms in the pathology following ICH remain unclear. The present study aimed to explore the effects of ILG after ICH and underlying mechanisms.MethodsICH model was induced by collagenase IV (0.2 U in 1 μl sterile normal saline) in male Sprague-Dawley rats weighing 280–320 g. Different doses of ILG (10, 20, or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling, respectively. Rats were intracerebroventricularly administrated with control scramble small interfering RNA (siRNA) or Nrf2 siRNA at 24 h before ICH induction, and after 24 h, ICH model was established with or without ILG (20 mg/kg) treatment. All rats were dedicated at 24 or 72 h after ICH. Neurological deficits, histological damages, brain water content (BWC), blood-brain barrier (BBB) disruption, and neuronal degeneration were evaluated; quantitative real-time RT-PCR (qRT-PCR), immunohistochemistry/immunofluorescence, western blot, and enzyme-linked immunosorbent assay (ELISA) were carried out; catalase, superoxide dismutase activities and reactive oxygen species (ROS), and glutathione/oxidized glutathione contents were measured.ResultsILG (20 and 40 mg/kg) markedly alleviated neurological deficits, histological damages, BBB disruption, brain edema, and neuronal degeneration, but there was no significant difference between two dosages. ILG (20 mg/kg) significantly suppressed the NF-κB and NLRP3 inflammasome pathways and activated Nrf2-mediated antioxidant system. Gene silencing of Nrf2 aggravated the neurological deficits, brain edema, and neuronal degeneration and increased the protein levels of NF-κB p65, NLRP3 inflammasome components, and IL-1β. ILG delivery significantly attenuated the effects of Nrf2 siRNA interference mentioned above.ConclusionsIntraperitoneal administration of ILG after ICH reduced early brain impairments and neurological deficits, and the mechanisms were involved in the regulation of ROS and/or NF-κB on the activation of NLRP3 inflammasome pathway by the triggering of Nrf2 activity and Nrf2-induced antioxidant system. In addition, our experimental results may make ILG a potential candidate for a novel therapeutical strategy for ICH.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0895-5) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Isoliquiritigenin alleviates early brain injury after experimental intracerebral hemorrhage via suppressing ROS- and/or NF-κB-mediated NLRP3 inflammasome activation by promoting Nrf2 antioxidant pathway

Zeng

Chen

Ding

et al. 2017

J Neuroinflammation

292

214

View full text Add to dashboard Cite

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“…The pathophysiology of ICH is characterized by the infiltration of systemic immune cells, the activation of microglia and the production of pro-inflammatory cytokines such as IL-1β (Wang and Doré, 2007). The expression of NLRP3 was increased in a mouse model of ICH, and the inhibition of NLRP3 attenuated neuroinflammation and improved neuronal function, which indicates the involvement of NLRP3 inflammasome in the pathogenesis of ICH (Ma et al, 2014; Yang et al, 2015; Yuan et al, 2015). ROS and the P2X purinergic receptor 7 (P2X7R) pathway may play roles in NLRP3 activation during ICH (Ma et al, 2014; Feng et al, 2015).…”

Section: Nlrp3 Inflammasome and Neurological Diseasesmentioning

confidence: 99%

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

Song

Pei

Yao

et al. 2017

Front. Cell. Neurosci.

363

275

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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.

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“…The extracellular innate immune sensors, such as TLRs, are responsible for receiving the extracellular signaling and activating the glial cells to produce a large number of pro-inflammatory cytokines after ICH (Akira and Takeda, 2004); while the intracellular innate immune sensors, such as NLRP3, NLRP6, etc., are responsible for processing the pro-IL-1β and pro-IL-18 into maturation state to exert important roles in cellular communications (Schroder and Tschopp, 2010; Strowig et al, 2012; Lamkanfi and Dixit, 2014). Previous studies have shown that the microglia-derived NLRP3 inflammasome was significantly increased and contributed to the inflammatory injury by releasing IL-1β and promoting neutrophil infiltration following ICH (Ma et al, 2014), and targeting the NLRP3 inflammasome could reduce the ICH-induced brain injury (Yang et al, 2015; Yuan et al, 2015). While, in our study, we found that the markedly increased NLRP6 inflammasome was mainly colocalized in the GFAP-positive astrocytes, with little expression in neurons while without expression in microglias after ICH, which was inconsistent with the expression profile of NLRP3 inflammasome after ICH (Ma et al, 2014), and we also found that NLRP6 deficiency resulted in the deterioration of the brain injury caused by ICH.…”

Section: Discussionmentioning

confidence: 99%

NLRP6 Inflammasome Ameliorates Brain Injury after Intracerebral Hemorrhage

Wang

Zhang

et al. 2017

Front. Cell. Neurosci.

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NLRP6 inflammasome, one of the important intracellular innate immune sensors, has been shown to regulate immune responses. However, its roles in the intracerebral hemorrhage (ICH) are completely not clear. In the present study, we investigated the expression profile and biological roles of NLRP6 inflammasome in perihematomal brain tissues of mice subjected to ICH. In this study, we investigated the expression profile of NLRP6 inflammasome in the perihematomal brain tissues and explored the biological role of NLRP6 inflammasome upon acute brain injury in mice subjected to ICH. Increased expression of NLRP6 inflammasome was found in perihematomal brain tissues ranging from 6 h to 3 days, with a peak level at 1 day after ICH. Immunohistochemistry staining also showed that NLRP6 inflammasome was significantly increased in the perihematomal brain tissues at 1 day after ICH. Moreover, immunofluorescence staining showed that NLRP6 inflammasome was mainly colocalized in glial fibrillary acidic protein (GFAP)-positive astrocytes, while with little colocalized expression in NeuN-positive neurons and without expression in CD11b-positive microglia and CD31-positive endothelial cell in the perihematomal brain tissue of mice after ICH. Furthermore, NLRP6−/− ICH mice exhibited significantly higher brain water contents (BMCs), proinflammatory cytokines, NF-κB activity and neurological deficit scores when compared with the wild type (WT) ICH mice. In addition, we found that Toll-like receptor 4 (TLR4)−/− mice, as well as the TAK242 treated mice, had markedly lower expression of NLRP6 inflammasome expression in the perihematomal brain tissue at 1 day after ICH. Our data suggest that the upregulated NLRP6 inflammasome in perihematomal brain tissues attenuates ICH-induced brain injury.

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Recombinant adenovirus encoding NLRP3 RNAi attenuate inflammation and brain injury after intracerebral hemorrhage

Cited by 41 publications

References 27 publications

Isoliquiritigenin alleviates early brain injury after experimental intracerebral hemorrhage via suppressing ROS- and/or NF-κB-mediated NLRP3 inflammasome activation by promoting Nrf2 antioxidant pathway

Isoliquiritigenin alleviates early brain injury after experimental intracerebral hemorrhage via suppressing ROS- and/or NF-κB-mediated NLRP3 inflammasome activation by promoting Nrf2 antioxidant pathway

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

NLRP6 Inflammasome Ameliorates Brain Injury after Intracerebral Hemorrhage

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