scholarly journals Leptin Induces Apoptotic and Pyroptotic Cell Death via NLRP3 Inflammasome Activation in Rat Hepatocytes

2021 ◽  
Vol 22 (22) ◽  
pp. 12589
Author(s):  
Ananda Baral ◽  
Pil-Hoon Park
Keyword(s):  
Cell Death ◽  
Rat Hepatocytes ◽  
Inflammasome Activation ◽  
Cytotoxic Effects ◽  
Nlrp3 Inflammasome Activation ◽  
Critical Components ◽  
Underlying Mechanisms ◽  
Nlrp3 Inflammasomes

Leptin, a hormone that is predominantly produced by adipose tissue, is closely associated with various liver diseases. However, there is a lack of understanding as to whether leptin directly induces cytotoxic effects in hepatocytes as well as the mechanisms that are involved. Inflammasomes, which are critical components in the innate immune system, have been recently shown to modulate cell death. In this study, we examined the effect of leptin on the viability of rat hepatocytes and the underlying mechanisms, with a particular focus on the role of inflammasomes activation. Leptin treatment induced cytotoxicity in rat hepatocytes, as determined by decreased cell viability, increased caspase-3 activity, and the enhanced release of lactate dehydrogenase. NLRP3 inflammasomes were activated by leptin both in vitro and in vivo, as determined by the maturation of interleukin-1β and caspase-1, and the increased expression of inflammasome components, including NLRP3 and ASC. Mechanistically, leptin-induced inflammasome activation is mediated via the axis of ROS production, ER stress, and autophagy. Notably, the inhibition of inflammasomes by treatment with the NLRP3 inhibitor or the IL-1 receptor antagonist protected the hepatocytes from leptin-induced cell death. Together, these results indicate that leptin exerts cytotoxic effects in hepatocytes, at least in part, via the activation of NLRP3 inflammasomes.

scholarly journals Koumine Suppresses IL-1β Secretion and Attenuates Inflammation Associated With Blocking ROS/NF-κB/NLRP3 Axis in Macrophages

2021 ◽  
Vol 11 ◽  
Author(s):  
Yufei Luo ◽  
Bojun Xiong ◽  
Haiping Liu ◽  
Zehong Chen ◽  
Huihui Huang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Inhibitory Effect ◽  
Receptor Protein ◽  
Mechanistic Study ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms

Koumine (KM), one of the primary constituents of Gelsemium elegans, has been used for the treatment of inflammatory diseases such as rheumatoid arthritis, but whether KM impacts the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome remains unknown. This study aimed to explore the inhibitory effect of KM on NLRP3 inflammasome activation and the underlying mechanisms both in vitro using macrophages stimulated with LPS plus ATP, nigericin or monosodium urate (MSU) crystals and in vivo using an MSU-induced peritonitis model. We found that KM dose-dependently inhibited IL-1β secretion in macrophages after NLRP3 inflammasome activators stimulation. Furthermore, KM treatment efficiently attenuated the infiltration of neutrophils and suppressed IL-1β production in mice with MSU-induced peritonitis. These results indicated that KM inhibited NLRP3 inflammasome activation, and consistent with this finding, KM effectively inhibited caspase-1 activation, mature IL-1β secretion, NLRP3 formation and pro-IL-1β expression in LPS-primed macrophages treated with ATP, nigericin or MSU. The mechanistic study showed that, KM exerted a potent inhibitory effect on the NLRP3 priming step, which decreased the phosphorylation of IκBα and p65, the nuclear localization of p65, and the secretion of TNF-α and IL-6. Moreover, the assembly of NLRP3 was also interrupted by KM. KM blocked apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and its oligomerization and hampered the NLRP3-ASC interaction. This suppression was attributed to the ability of KM to inhibit the production of reactive oxygen species (ROS). In support of this finding, the inhibitory effect of KM on ROS production was completely counteracted by H2O2, an ROS promoter. Our results provide the first indication that KM exerts an inhibitory effect on NLRP3 inflammasome activation associated with blocking the ROS/NF-κB/NLRP3 signal axis. KM might have potential clinical application in the treatment of NLRP3 inflammasome-related diseases.

scholarly journals Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Bora Tastan ◽  
Burak I. Arioz ◽  
Kemal Ugur Tufekci ◽  
Emre Tarakcioglu ◽  
Ceren Perihan Gonul ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Forced Swim Test ◽  
Sickness Behavior ◽  
Dimethyl Fumarate ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

NLRP3 inflammasome activation contributes to several pathogenic conditions, including lipopolysaccharide (LPS)-induced sickness behavior characterized by reduced mobility and depressive behaviors. Dimethyl fumarate (DMF) is an immunomodulatory and anti-oxidative molecule commonly used for the symptomatic treatment of multiple sclerosis and psoriasis. In this study, we investigated the potential use of DMF against microglial NLRP3 inflammasome activation both in vitro and in vivo. For in vitro studies, LPS- and ATP-stimulated N9 microglial cells were used to induce NLRP3 inflammasome activation. DMF’s effects on inflammasome markers, pyroptotic cell death, ROS formation, and Nrf2/NF-κB pathways were assessed. For in vivo studies, 12–14 weeks-old male BALB/c mice were treated with LPS, DMF + LPS and ML385 + DMF + LPS. Behavioral tests including open field, forced swim test, and tail suspension test were carried out to see changes in lipopolysaccharide-induced sickness behavior. Furthermore, NLRP3 and Caspase-1 expression in isolated microglia were determined by immunostaining. Here we demonstrated that DMF ameliorated LPS and ATP-induced NLRP3 inflammasome activation by reducing IL-1β, IL-18, caspase-1, and NLRP3 levels, reactive oxygen species formation and damage, and inhibiting pyroptotic cell death in N9 murine microglia via Nrf2/NF-κB pathways. DMF also improved LPS-induced sickness behavior in male mice and decreased caspase-1/NLRP3 levels via Nrf2 activation. Additionally, we showed that DMF pretreatment decreased miR-146a and miR-155 both in vivo and in vitro. Our results proved the effectiveness of DMF on the amelioration of microglial NLRP3 inflammasome activation. We anticipate that this study will provide the foundation consideration for further studies aiming to suppress NLRP3 inflammasome activation associated with in many diseases and a better understanding of its underlying mechanisms.

scholarly journals H3 Relaxin Alleviates Migration, Apoptosis and Pyroptosis Through P2X7R-Mediated Nucleotide Binding Oligomerization Domain-Like Receptor Protein 3 Inflammasome Activation in Retinopathy Induced by Hyperglycemia

2020 ◽  
Vol 11 ◽  
Author(s):  
Kelaier Yang ◽  
Jiannan Liu ◽  
Xiaohui Zhang ◽  
Ziqi Ren ◽  
Lei Gao ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inhibitory Effect ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Sprague Dawley ◽  
Nlrp3 Inflammasome Activation ◽  
Underlying Mechanisms ◽  
And Migration

Introduction: P2X7R excitation-interrelated NLRP3 inflammasome activation induced by high glucose contributes to the pathogenesis of diabetic retinopathy (DR). Relaxin-3 is a bioactive peptide with a structure similar to insulin, which has been reported to be effective in diabetic cardiomyopathy models in vivo and in vitro. However, it is not known whether relaxin-3 has a beneficial impact on DR, and the underlying mechanisms of the effect are also remain unknown.Methods and Results: The retinas of male streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats were characterized. Human retinal microvascular endothelial cells (HRMECs) were used to evaluate the anti-inflammatory, antiapoptotic, antipyroptotic and anti-migration effects of H3 relaxin by transmission electron microscopy, wound-healing assay, transwell assay, flow cytometry, cytokine assays and western-blot analysis. After H3 relaxin treatment, changes of the ultrastructure and expression of NLRP3 inflammasome related proteins in the retinas of rats were compared with those in the diabetic group. In vitro, H3 relaxin played a beneficial role that decreased cell inflammation, apoptosis, pyroptosis and migration stimulated by advanced glycation end products (AGEs). Moreover, inhibition of P2X7R and NLRP3 inflammasome activation decreased NLRP3 inflammasome-mediated injury that similar to the effects of H3 relaxin. H3 relaxin suppressed the stimulation of apoptosis, pyroptosis and migration of HRMECs in response to AGEs mediated by P2X7R activation of the NLRP3 inflammasome.Conclusion: Our findings provide new insights into the mechanisms of the inhibitory effect of H3 relaxin on AGE-induced retinal injury, including migration, apoptosis and pyroptosis, mediated by P2X7R-dependent activation of the NLRP3 inflammasome in HRMECs.

Pharmacological Blocker of NF-κb and Mitochondrial Ros Restrict NLRP3 Inflammasome Activation and Rescue Dopaminergic Neurons in Vitro and in Vivo Parkinson’s Disease

2021 ◽  
Author(s):  
Sahabuddin Ahmed ◽  
Samir Ranjan Panda ◽  
Mohit Kwatra ◽  
Bidya Dhar Sahu ◽  
VGM Naidu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Free Radicals ◽  
Nlrp3 Inflammasome ◽  
Nuclear Translocation ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation

Abstract Several activators of NLRP3 inflammasome have been described; however, the central mechanisms of NLRP3 inflammasome activation in brain microglia, especially at the activating step through free radical generation, still require further clarification. Hence the present study aimed to investigate the role of free radicals in activating NLRP3 inflammasome driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in vitro and in vivo models of Parkinson’s disease. Initial priming of microglial cells with lipopolysaccharide (LPS) following treatment with hydrogen peroxide (H2O2) induces NF-κB translocation to nucleus with robust generation of free radicals that act as Signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses nuclear translocation of NF-κB and maintains cellular redox homeostasis in microglia that limits NLRP3 inflammasome activation along with processing active caspase-1, IL-1β and IL-18. To further correlates the in vitro study with in vivo MPTP model, treatment with PA also inhibits the nuclear translocation of NF-κB and downregulates the NLRP3 inflammasome activation. PA administration upregulates various antioxidant enzymes levels and restored the level of dopamine and other neurotransmitters in the striatum of the mice brain with improved behavioural activities. Additionally, treatment with Mito-TEMPO (a mitochondrial ROS inhibitor) was also seen to inhibit NLRP3 inflammasome and rescue dopaminergic neuron loss in the mice brain. Therefore, we conclude that NLRP3 inflammasome activation requires a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting NLRP3 inflammasome pathway in Parkinson’s disease.

Abstract P259: Endothelial Acid Sphingomyelinase Gene Determines Inflammasome Activation and Atherosclerotic Lesions in Carotid Arteries During Hypercholesterolemia

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Min Xia ◽  
Krishna M Bioni ◽  
Yang Chen ◽  
Xiang Li ◽  
Ashley L Pitzer ◽  
...  
Keyword(s):  
Carotid Arteries ◽  
Acid Sphingomyelinase ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Neointimal Formation ◽  
Atherosclerotic Lesions ◽  
Junction Protein ◽  
Nlrp3 Inflammasomes

Nucleotide oligomerization domain (NOD)-like receptor protein with pyrin domain containing 3 (Nlrp3) inflammasome has been reported to be activated by atherogenic factors, thereby triggering endothelial injury and consequent atherosclerotic lesions in the arterial wall. However, the mechanism activating and regulating Nlrp3 inflammasomes remains poorly understood. The present study tested whether membrane raft (MR) signaling platforms associated with acid sphingomyelinase (ASM) and its product ceramide (Ce) importantly contribute to the activation of Nlrp3 inflammasomes and atherosclerotic lesions during hypercholesterolemia (HC). By confocal microscopy and biochemical analyses, we demonstrated the formation and activation of Nlrp3 inflammasomes in the intima of the carotid arteries of Asm +/+ mice with HC (as shown by a 2-fold increase in caspase-1 activity and a 6-fold enhancement of IL-1β positive stain areas), but not in Asm -/- mice. In endothelium-specific ASM transgenic mice (EC-Asm trg ), this inflammasome formation and activation were enhanced. Correspondingly, HC-induced increases in IL-1β production, ASM expression, Ce level and MR-gp91 phox clustering in the carotid intima were abolished in Asm -/- mice, but enhanced in EC-Asm trg mice. Functionally, endothelium-dependent vasodilation (EDVD) in carotid arteries in vivo (by ultrasound flowmetry) and in vitro (in perfused artery) was impaired by HC in Asm +/+ mice by 33% and 54%, respectively. This endothelial dysfunction was not observed in Asm -/- mice. The endothelial tight junction protein, ZO-1 was reduced by HC in both Asm +/+ and EC-Asm trg mice, but not in Asm -/- mice. It was also found that HC-increased neointimal formation, T-cell infiltration, and fibrosis in 2-week partially ligated carotid arteries (PLCA) occurred in Asm +/+ mice, but not in Asm -/- mice with HC. EC-Asm trg mice even exhibited more severe inflammatory and atherosclerotic lesions. All these results suggest that Asm gene and related MR clustering are essential to endothelial inflammasome activation and dysfunction in carotid arteries, ultimately determining the extent of atherosclerotic lesions.

Kaempferol Alleviates Corneal Transplantation Rejection by Inhibiting NLRP3 Inflammasome Activation and Macrophage M1 Polarization via Promoting Autophagy

2021 ◽  
Author(s):  
Huiwen Tian ◽  
Shumei Lin ◽  
Jing Wu ◽  
Ming Ma ◽  
Jian Yu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Macrophage Polarization ◽  
Corneal Transplantation ◽  
Inflammasome Activation ◽  
M1 Polarization ◽  
Nlrp3 Inflammasome Activation ◽  
M1 Macrophage ◽  
Transplantation Rejection

Abstract Corneal transplantation rejection remains a major threat to the success rate in high-risk patients. Given the many side effects presented by traditional immunosuppressants, there is an urgency to clarify the mechanism of corneal transplantation rejection and to identify new therapeutic targets. Kaempferol is a natural flavonoid that has been proven in various studies to possess anti-inflammatory, antioxidant, anticancer, and neuroprotective properties. However, the relationship between kaempferol and corneal transplantation remains largely unexplored. To address this, both in vivo and in vitro, we established a model of corneal allograft transplantation in Wistar rats and an LPS-induced inflammatory model in THP-1 derived human macrophages. In the transplantation experiments, we observed an enhancement in the NLRP3 / IL-1 β axis and in M1 macrophage polarization post-operation. In groups to which kaempferol intraperitoneal injections were administered, this response was effectively reduced. However, the effect of kaempferol was reversed after the application of autophagy inhibitors. Similarly, in the inflammatory model, we found that different concentrations of kaempferol can reduce the LPS-induced M1 polarization and NLRP3 inflammasome activation. Moreover, we confirmed that kaempferol induced autophagy and that autophagy inhibitors reversed the effect in macrophages. In conclusion, we found that kaempferol can inhibit the activation of the NLRP3 inflammasomes by inducing autophagy, thus inhibiting macrophage polarization, and ultimately alleviating corneal transplantation rejection. Thus, our study suggests that kaempferol could be used as a potential therapeutic agent in the treatment of allograft rejection.

In Vivo Interactions with (Tissue Culture Pretreated) Dermal Sheep Collagen

1991 ◽  
Vol 252 ◽  
Author(s):  
P. B. van Wachem ◽  
P. B. van Wachem ◽  
L. H. H. Olde Damink ◽  
P. J. Dijkstra ◽  
J. Feijen ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Cell Death ◽  
Marked Reduction ◽  
Giant Cells ◽  
In Vitro Cytotoxicity ◽  
Cell Infiltration ◽  
Cytotoxic Effects ◽  
Lipid Formation

ABSTRACTPretreatment in tissue culture (TC) was previously found to markedly reduce the in vitro cytotoxicity of two types of crosslinked dermal sheep collagens (DSC's). This in vivo study confirms our in vitro results, in that TC-pretreatment of crosslinked DSC's resulted in the marked reduction or elimination of cytotoxic effects, such as increased cell infiltration, a deviant neutrophil-morphology, lipid formation and cell death. TC-pretreatment affected the crosslinked state of both DSC's in a different way, which could be deduced from the differences in gelatin-formation and presence of giant cells from macrophage- or fibroblast-origin. The results are explained in view of the differences in crosslinking.

scholarly journals The Essential Oil of Artemisia argyi H.Lév. and Vaniot Attenuates NLRP3 Inflammasome Activation in THP-1 Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Pengxiao Chen ◽  
Qi Bai ◽  
Yanting Wu ◽  
Qiongzhen Zeng ◽  
Xiaowei Song ◽  
...  
Keyword(s):  
Essential Oil ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Artemisia Argyi ◽  
Nlrp3 Inflammasome Activation ◽  
Long Time

Artemisia argyi H. Lév. and Vaniot is a traditional medical herb that has been used for a long time in China and other Asian counties. Essential oil is the main active fraction of Artemisia argyi H. Lév. and Vaniot, and its anti-inflammatory potential has been observed in vitro and in vivo. Here, we found that the essential oil of Artemisia argyi H. Lév. and Vaniot (EOAA) inhibited monosodium urate (MSU)- and nigericin-induced NLRP3 inflammasome activation. EOAA suppressed caspase-1 and IL-1β processing and pyroptosis. NF-κB p65 phosphorylation and translocation were also inhibited. In addition, EOAA suppressed nigericin-induced NLRP3 inflammasome activation without blocking ASC oligomerization, suggesting that it may inhibit NLRP3 inflammasome activation by preventing caspase-1 processing. Our study thus indicates that EOAA inhibits NLRP3 inflammasome activation and has therapeutic potential against NLRP3-driven diseases.

scholarly journals Vaspin Alleviates Osteoarthritis by Inhibiting NLRP3-mediated Inflammation

2021 ◽  
Author(s):  
Xianjie Zhu ◽  
Shiyou Dai ◽  
Baohua Xia ◽  
Jianbao Gong ◽  
Bingzheng Ma
Keyword(s):  
Nlrp3 Inflammasome ◽  
Wistar Rat ◽  
Cartilage Degradation ◽  
Pathological Process ◽  
Inflammasome Activation ◽  
Protective Effects ◽  
Collagen Formation ◽  
Nlrp3 Inflammasome Activation

Abstract Background:Osteoarthritis (OA) is a chronic degenerative joint bone disease characterized by cartilage degradation. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is associated with the inflammatory and metabolic responses to OA. However, the underlying mechanisms of the pathological process of OA are not clear. The aim of the present study was to examine the protective effects of vaspin both in vitro and in vivo.Methods:Monosodium iodoacetate (MIA)-induced Wistar rat model of OA was used to assess the in vivo effects of vaspin administered for 12 weeks. The characteristics of OA were evaluated by haematoxylin and eosin (H&E) and safranin O/fast green staining. The anti-inflammatory effect of vaspin was assessed using immunohistochemical, qRT-PCR, and western blotting analysis. Parallel experiments to detect the molecular mechanism through which vaspin prevents OA were performed using LPS-treated chondrocytes.Results:Our results showed that the degeneration of cartilage and upregulated expression of matrix metalloproteinase (MMP)-1 and MMP-13 were ameliorated by vaspin. Additionally, vaspin suppressed the activation of TXNIP/NLRP3 and secretion of tumor necrosis factor ɑ and interleukin-1β in vivo. It was further confirmed that vaspin could also suppress LPS-induced NLRP3 inflammasome activation and reduce collagen formation in chondrocytes. Moreover, vaspin inhibited NLRP3 inflammasome activation by suppressing the ROS/TXNIP pathway.Conclusions: Vaspin inhibited OA by repressing TXNIP/NLRP3 activation in in vitro and in vivo models of OA, thus providing a novel therapeutic strategy for OA.

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