scholarly journals SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage

2021 ◽  
Vol 12 ◽  
Author(s):  
Da-Yong Xia ◽  
Jin-Long Yuan ◽  
Xiao-Chun Jiang ◽  
Min Qi ◽  
Nian-Sheng Lai ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Oxidative Damage ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Neuronal Degeneration ◽  
Sirtuin 1 ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Microglia Polarization ◽  
M1 Phenotype

Mounting evidence has suggested that modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state might be a potential therapeutic approach in the treatment of subarachnoid hemorrhage (SAH) injury. Our previous study has indicated that sirtuin 1 (SIRT1) could ameliorate early brain injury (EBI) in SAH by reducing oxidative damage and neuroinflammation. However, the effects of SIRT1 on microglial polarization and the underlying molecular mechanisms after SAH have not been fully illustrated. In the present study, we first observed that EX527, a potent selective SIRT1 inhibitor, enhanced microglial M1 polarization and nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in microglia after SAH. Administration of SRT1720, an agonist of SIRT1, significantly enhanced SIRT1 expression, improved functional recovery, and ameliorated brain edema and neuronal death after SAH. Moreover, SRT1720 modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, SRT1720 significantly decreased acetylation of forkhead box protein O1, inhibited the overproduction of reactive oxygen species (ROS) and suppressed NLRP3 inflammasome signaling. In contrast, EX527 abated the upregulation of SIRT1 and reversed the inhibitory effects of SRT1720 on ROS-NLRP3 inflammasome activation and EBI. Similarly, in vitro, SRT1720 suppressed inflammatory response, oxidative damage, and neuronal degeneration, and improved cell viability in neurons and microglia co-culture system. These effects were associated with the suppression of ROS-NLRP3 inflammasome and stimulation of SIRT1 signaling, which could be abated by EX527. Altogether, these findings indicate that SRT1720, an SIRT1 agonist, can ameliorate EBI after SAH by shifting the microglial phenotype toward M2 via modulation of ROS-mediated NLRP3 inflammasome signaling.

scholarly journals Luteolin Confers Cerebroprotection after Subarachnoid Hemorrhage by Suppression of NLPR3 Inflammasome Activation through Nrf2-Dependent Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Zi-Huan Zhang ◽  
Jia-Qiang Liu ◽  
Cheng-Di Hu ◽  
Xin-Tong Zhao ◽  
Fei-Yun Qin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Subarachnoid Hemorrhage ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Neuronal Degeneration ◽  
Antioxidant Systems ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Beneficial Effects ◽  
Nrf2 Activation

Luteolin (LUT) possesses multiple biologic functions and has beneficial effects for cardiovascular and cerebral vascular diseases. Here, we investigated the protective effects of LUT against subarachnoid hemorrhage (SAH) and the involvement of underlying molecular mechanisms. In a rat model of SAH, LUT significantly inhibited SAH-induced neuroinflammation as evidenced by reduced microglia activation, decreased neutrophil infiltration, and suppressed proinflammatory cytokine release. In addition, LUT markedly ameliorated SAH-induced oxidative damage and restored the endogenous antioxidant systems. Concomitant with the suppressed oxidative stress and neuroinflammation, LUT significantly improved neurologic function and reduced neuronal cell death after SAH. Mechanistically, LUT treatment significantly enhanced the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), while it downregulated nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation. Inhibition of Nrf2 by ML385 dramatically abrogated LUT-induced Nrf2 activation and NLRP3 suppression and reversed the beneficial effects of LUT against SAH. In neurons and microglia coculture system, LUT also mitigated oxidative stress, inflammatory response, and neuronal degeneration. These beneficial effects were associated with activation of the Nrf2 and inhibitory effects on NLRP3 inflammasome and were reversed by ML385 treatment. Taken together, this present study reveals that LUT confers protection against SAH by inhibiting NLRP3 inflammasome signaling pathway, which may be modulated by Nrf2 activation.

scholarly journals Tetrandrine alleviates cerebral ischemia/reperfusion injury by suppressing NLRP3 inflammasome activation via Sirt-1

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9042
Author(s):  
Jun Wang ◽  
Ming Guo ◽  
Ruojia Ma ◽  
Maolin Wu ◽  
Yamei Zhang
Keyword(s):  
Cerebral Ischemia ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Sirtuin 1 ◽  
Neurological Deficits ◽  
Inflammasome Activation ◽  
Cerebral Ischemia Reperfusion ◽  
Nlrp3 Inflammasome Activation

Background & Aims Tetrandrine (Tet) has been reported to have anti-inflammatory effects and protect from the ischemic strokes. The NLRP3 inflammasome plays a key role in cerebral ischemia/reperfusion (I/R)-induced inflammatory lesions. However, the molecular mechanisms of Tet related to the progression of cerebral ischemia are still unclear. Therefore, the aim of this study was to investigate the possible effects of Tet on cerebral ischemia and the related mechanisms involved in NLRP3 inflammasome. Methods C57BL/6J mice used as a cerebral I/R injury model underwent middle cerebral artery occlusion (MCAO) for 2 h following reperfusion for 24 h. Tet (30 mg/kg/day, i.p.) was administered for seven days and 30 min before and after MCAO. Their brain tissues were evaluated for NLRP3 inflammasome and Sirtuin-1 (Sirt-1) expression. An intracerebroventricular injection of Sirt-1 siRNA was administered to assess the activation of the NLRP3 inflammasome. Results Tet significantly reduced the neurological deficits, infarction volume, and cerebral water content in MCAO mice. Moreover, it inhibited I/R-induced over expression of NLRP3, cleaved caspase-1, interleukin (IL)-1β, IL-18, and Sirt-1. Sirt-1 knockdown with siRNA greatly blocked the Tet-induced reduction of neurological severity score and infarct volume, and reversed the inhibition of NLRP3 inflammasome activation. Conclusion Our results demonstrate that Tet has benefits for cerebral I/R injury, which are partially related to the suppression of NLRP3 inflammasome activation via upregulating Sirt-1.

scholarly journals Bushen-Yizhi Formula Alleviates Neuroinflammation via Inhibiting NLRP3 Inflammasome Activation in a Mouse Model of Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Yousheng Mo ◽  
Erjin Xu ◽  
Renrong Wei ◽  
Baoluu Le ◽  
Lei Song ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Neuronal Degeneration ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Neuroprotective Effects ◽  
Nlrp3 Inflammasome Activation

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Although the molecular mechanisms underlying dopaminergic neuronal degeneration in PD remain unclear, neuroinflammation is considered as the vital mediator in the pathogenesis and progression of PD. Bushen-Yizhi Formula (BSYZ), a traditional Chinese medicine, has been demonstrated to exert antineuroinflammation in our previous studies. However, it remains unclear whether BSYZ is effective for PD. Here, we sought to assess the neuroprotective effects and explore the underlying mechanisms of BSYZ in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine- (MPTP-) induced mouse model of PD. Our results indicate that BSYZ significantly alleviates the motor impairments and dopaminergic neuron degeneration of MPTP-treated mice. Furthermore, BSYZ remarkably attenuates microglia activation, inhibits NLPR3 activation, and decreases the levels of inflammatory cytokines in MPTP-induced mouse brain. Also, BSYZ inhibits NLRP3 activation and interleukin-1βproduction of the 1-methyl-4-phenyl-pyridinium (MPP+) stimulated BV-2 microglia cells. Taken together, our results indicate that BSYZ alleviates MPTP-induced neuroinflammation probably via inhibiting NLRP3 inflammasome activation in microglia. Collectively, BSYZ may be a potential therapeutic agent for PD and the related neurodegeneration diseases.

scholarly journals Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy Following Ischemic Brain Injury

2020 ◽  
Vol 21 (11) ◽  
pp. 3740 ◽  
Author(s):  
Claudia Espinosa-Garcia ◽  
Fahim Atif ◽  
Seema Yousuf ◽  
Iqbal Sayeed ◽  
Gretchen N. Neigh ◽  
...  
Keyword(s):  
Brain Injury ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Global Ischemia ◽  
Inflammasome Activation ◽  
Ischemic Brain Injury ◽  
Primary Microglia ◽  
Ischemic Brain ◽  
Nlrp3 Inflammasome Activation ◽  
The Impact

NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1β production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1β production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone’s (PROG’s) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.

scholarly journals Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Ziwei Xu ◽  
Zi-mo Chen ◽  
Xiaoyan Wu ◽  
Linjie Zhang ◽  
Ying Cao ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Inflammasome Activation ◽  
Potassium Efflux ◽  
Pannexin 1 ◽  
Nlrp3 Inflammasome Activation ◽  
K2p Channels ◽  
Pore Forming Proteins ◽  
Molecular Patterns

The NLRP3 inflammasome is a core component of innate immunity, and dysregulation of NLRP3 inflammasome involves developing autoimmune, metabolic, and neurodegenerative diseases. Potassium efflux has been reported to be essential for NLRP3 inflammasome activation by structurally diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Thus, the molecular mechanisms underlying potassium efflux to activate NLRP3 inflammasome are under extensive investigation. Here, we review current knowledge about the distinction channels or pore-forming proteins underlying potassium efflux for NLRP3 inflammasome activation with canonical/non-canonical signaling or following caspase-8 induced pyroptosis. Ion channels and pore-forming proteins, including P2X7 receptor, Gasdermin D, pannexin-1, and K2P channels involved present viable therapeutic targets for NLRP3 inflammasome related diseases.

scholarly journals Modulation of RAS and PI3-AKT pathway by Stavudine (d4T) in PBMC of Alzheimer’s Disease Patients

2020 ◽  
Author(s):  
Francesca La Rosa ◽  
Chiara Paola Zoia ◽  
Chiara Bazzini ◽  
Alessandra Bolognini ◽  
Saresella Marina ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Beclin 1 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Beneficial Effects ◽  
Nlrp3 Inflammasome Activation ◽  
Chaperone Mediated Autophagy ◽  
Inflammasome Activity

Abstract Background Aβ42-deposition plays a pivotal role in AD-pathogenesis by inducing the activation of microglial cells and neuroinflammation. This process is antagonized by microglia-mediated clearance of Aβ plaques. Activation of the NLRP3 inflammasome is involved in neuroinflammation and in the impairments of Aβ-plaques clearance. Stavudine (d4T) on the other hand down-regulates the NLRP3 inflammasome and stimulates autophagy-mediated Aβ-clearing in a TPH-1 cell line model. Methods We explored the effect of d4T on Aβ- autophagy using PBMC of AD patients that were primed with LPS and stimulated with Aβ in the absence/presence of d4T. We analyzed the NLRP3 inflammasome activity by measuring NLRP3-ASC complexes formation by AMNIS Flow-sight and pro-inflammatory cytokines (IL-1β, IL-18 and Caspase-1) production by enzyme-linked immunosorbent assay (ELISA). Western blot analyses were used to measure phosphorylation and protein expression of p38, CREB, ERK and AKT, p70, LAMP 2A, beclin-1 and Bax. Results data showed that d4T: 1) down regulates NLRP3 inflammasome activation and the production of down-stream proinflammatory cytokines even in PBMC; 2) stimulates the phosphorylation of AKT, ERK, p70 as well as LAMP2A production, but does modulate beclin-1, suggesting a selective effect of this compound on chaperone-mediated autophagy (CMA); 3) up regulates p-CREB and BAX, possibly diminishing Aβ–mediated cytotoxicity; and 4) reduces the phosphorylation of p-38, a protein involved in the production of proinflammatory cytokines. Conclusions d4T reduces the activation of the NLRP3 inflammasome and stimulates CMA autophagy as well as molecular mechanisms that modulate cytotoxicity and reduce inflammation in cells of AD patients. It might be interesting to verify the possibly beneficial effects of d4T in the clinical scenario.

RIP1-RIP3-DRP1 pathway regulates NLRP3 inflammasome activation following subarachnoid hemorrhage

2017 ◽  
Vol 295 ◽  
pp. 116-124 ◽  
Author(s):  
Keren Zhou ◽  
Ligen Shi ◽  
Zhen Wang ◽  
Jingyi Zhou ◽  
Anatol Manaenko ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

scholarly journals Targeting NLRP3 Inflammasome Activation in Severe Asthma

2019 ◽  
Vol 8 (10) ◽  
pp. 1615 ◽  
Author(s):  
Efthymia Theofani ◽  
Maria Semitekolou ◽  
Ioannis Morianos ◽  
Konstantinos Samitas ◽  
Georgina Xanthou
Keyword(s):  
Severe Asthma ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Reversible Airflow Obstruction

Severe asthma (SA) is a chronic lung disease characterized by recurring symptoms of reversible airflow obstruction, airway hyper-responsiveness (AHR), and inflammation that is resistant to currently employed treatments. The nucleotide-binding oligomerization domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome is an intracellular sensor that detects microbial motifs and endogenous danger signals and represents a key component of innate immune responses in the airways. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18 as well as pyroptosis. Accumulating evidence proposes that NLRP3 activation is critically involved in asthma pathogenesis. In fact, although NLRP3 facilitates the clearance of pathogens in the airways, persistent NLRP3 activation by inhaled irritants and/or innocuous environmental allergens can lead to overt pulmonary inflammation and exacerbation of asthma manifestations. Notably, administration of NLRP3 inhibitors in asthma models restrains AHR and pulmonary inflammation. Here, we provide an overview of the pathophysiology of SA, present molecular mechanisms underlying aberrant inflammatory responses in the airways, summarize recent studies pertinent to the biology and functions of NLRP3, and discuss the role of NLRP3 in the pathogenesis of asthma. Finally, we contemplate the potential of targeting NLRP3 as a novel therapeutic approach for the management of SA.

scholarly journals Leptin Signalling in the Ovary of Diet-Induced Obese Mice Regulates Activation of Nod-Like Receptor Protein 3 Inflammasome

2021 ◽  
Author(s):  
Marek Adamowski ◽  
Karolina Wolodko ◽  
Joana Oliveira ◽  
Juan Castillo-Fernandez ◽  
Daniel Murta ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Maternal Obesity ◽  
Cumulus Cells ◽  
Leptin Resistance ◽  
Receptor Protein ◽  
Chow Diet ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

Obesity leads to ovarian dysfunction and the establishment of local leptin resistance. The aim of our study was to characterise levels of Nod-Like Receptor Protein 3 (NLRP3) inflammasome activation during obesity progression in the mouse ovaries and liver and test the putative role of leptin on its regulation. C57BL/6J mice were treated with equine chorionic gonadotropin (eCG) or human chorionic gonadotropin (hCG) for oestrous cycle synchronisation and ovaries collection. In diet-induced obesity (DIO) model, mice were fed chow diet (CD) or high fat diet (HFD) for 4 or 16 weeks (wk), whereas in hyperleptinemic model (LEPT), mice were injected with leptin for 16 days (16L) or saline (16C) and in the genetic obese leptin-deficient ob/ob (+/? and -/-) animals were fed CD for 4wk. Either ovaries and liver were collected, as well as cumulus cells (CCs) after superovulation from DIO and LEPT. In DIO protocol, protein expression of NLRP3 inflammasome components was increased in 4wk HFD, but decreased in 16wk HFD. Moreover LEPT and ob/ob models revealed NLRP3 and IL-1b; upregulation in 16L and downregulation in ob/ob. Transcriptome analysis of CC showed common genes between LEPT and 4wk HFD modulating NLRP3 inflammasome. Moreover analysis in the liver showed upregulation of NLRP3 protein only after 16wk HFD, but also the downregulation of NLRP3 protein in ob/ob-/-. We showed the link between leptin signalling and NLRP3 inflammasome activation in the ovary throughout obesity progression in mice, elucidating the molecular mechanisms underpinning ovarian failure in maternal obesity.

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