The Potential Role of the NLRP3 Inflammasome Activation as a Link Between Mitochondria ROS Generation and Neuroinflammation in Postoperative Cognitive Dysfunction

Diabetes is associated with a high risk of developing cognitive dysfunction and neuropsychiatric disabilities, and these disease symptomsare termed diabetic encephalopathy (DEP). Inflammation is involved in the development of DEP. The cleavage and maturation of the proinflammatory cytokine interleukin (IL)-1β is regulated by the NLRP3 inflammasome. Obese and type 2 diabetic db/db mice show anxiety- and depression-like behaviors and cognitive disorders associated with hippocampal inflammation. The purpose of this study was to explore the role of NLRP3 inflammasome in DEP. Results showed that expression levels of inflammasome components including NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1, as well as IL-1β in the hippocampus of diabetic db/db mice were higher than those of non-diabetic db/m mice. Treatment of db/db mice with NLRP3 inflammasome inhibitor MCC950 ameliorated anxiety- and depression-like behaviors as well as cognitive dysfunction, and reversed increased NLRP3, ASC, and IL-1βexpression levels and caspase-1 activity in hippocampus. Moreover, MCC950 treatment significantly improved insulin sensitivity in db/db mice. These results demonstrate that inhibition of NLRP3 inflammasome activation may prove to be a potential therapeutic approach for DEP treatment.

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Abstract 96: Melatonin Prevents Atherosclerosis via Regulating NLRP3 Inflammasome: The Role of Sirt3 Signaling

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.96 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Sai Ma ◽

Jiangwei Chen ◽

Zhenli Luo ◽

Yabin Wang ◽

Feng Cao

Keyword(s):

Protective Effect ◽

Signaling Pathway ◽

Nlrp3 Inflammasome ◽

Inflammatory Factors ◽

Ros Generation ◽

Inflammasome Activation ◽

Mitochondrial Ros ◽

Nlrp3 Inflammasome Activation

Introduction: NLRP3 inflammasome mediated inflammatory factors secretion is critically involved in atherosclerosis (AS). Melatonin has anti-inflammatory properties. However, it is unknown whether melatonin is beneficial in AS. Hypothesis: Melatonin plays a beneficial role in AS by decreasing NLRP3 inflammasome activation in macrophages. Methods: AS model was induced with high fat diet in apoE -/- mice. Plaque stability was examined with historical staining. In vitro study was performed in ox-LDL treated RAW264.7 cells. NLRP3 inflammasome activation, inflammatory factors secretion, mitochondrial ROS generation, autophagy, mitophagy indexes and potential signaling pathways were investigated. Results: Historical staining results showed that melatonin treatment markedly alleviated AS plaque progression. Despite of unchanged protein expression, Sirt 3 activity was elevated in plaque tissue in melatonin treated mice. Melatonin attenuated NLRP3 inflammasome activation and inflammatory factors secretion in ox-LDL treated macrophages, while this protective effect was abolished by Sirt3-siRNA. Mitochondrial ROS (mitoROS), which was an inducer for NLRP3 inflammasome, was reduced by melatonin through the elimination of damaged mitochondria (mitophagy). Similar with Sirt3-siRNA, autophagy inhibitor 3-MA also abolished the effects of melatonin on mitoROS clearance, indicating the crucial role of autophagy and mitophagy in melatonin caused NLRP3 inactivation. Furthermore, melatonin protected against AS via Sirt3/FoxO3/Parkin signaling pathway. Conclusions: Melatonin prevented atherosclerotic progression. Melatonin reduced mitochondrial ROS through the activation of autophagy and mitophagy, thereby attenuating NLRP3 inflammasome activation in macrophages. Moreover, the protective effect of melatonin was mediated by Sirt3/FoxO3/Parkin signaling pathway. Our study provides insight into a new therapeutic target for AS.

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Role of mitochondria ROS generation in ethanol-induced NLRP3 inflammasome activation and cell death in astroglial cells

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2014.00216 ◽

2014 ◽

Vol 8 ◽

Cited By ~ 112

Author(s):

Silvia Alfonso-Loeches ◽

Juan R. UreÃ±a-Peralta ◽

Maria JosÃ© Morillo-Bargues ◽

Jorge Oliver-De La Cruz ◽

Consuelo Guerri

Keyword(s):

Cell Death ◽

Nlrp3 Inflammasome ◽

Ros Generation ◽

Inflammasome Activation ◽

Astroglial Cells ◽

Nlrp3 Inflammasome Activation

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Faculty Opinions recommendation of The role of lysosomal cysteine cathepsins in NLRP3 inflammasome activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.735165969.793559816 ◽

2019 ◽

Author(s):

Paras Anand

Keyword(s):

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Cysteine Cathepsins ◽

Nlrp3 Inflammasome Activation

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Inhibition of NLRP3 inflammasome activation and pyroptosis with ethyl acetate fraction of Bungeanum ameliorated cognitive dysfunction in aged mice

Food & Function ◽

10.1039/d1fo00876e ◽

2021 ◽

Author(s):

Meihuan Zhao ◽

Yuan Dai ◽

Ping Li ◽

Jie wang ◽

Tengyun Ma ◽

...

Keyword(s):

Ethyl Acetate ◽

Cognitive Dysfunction ◽

Nlrp3 Inflammasome ◽

Ethyl Acetate Fraction ◽

Inflammasome Activation ◽

Material Basis ◽

Age Related ◽

Nlrp3 Inflammasome Activation ◽

Zanthoxylum Bungeanum ◽

Zanthoxylum Bungeanum Maxim

Zanthoxylum bungeanum Maxim (Rutaceae), a homologous of medicine and foodstuff, has previously been demonstrated the potential prevention of age-related cognitive dysfunction. However, the mechanisms and material basis remain elusively understood....

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The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

Mediators of Inflammation ◽

10.1155/2013/678627 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 48

Author(s):

Elisa Benetti ◽

Fausto Chiazza ◽

Nimesh S. A. Patel ◽

Massimo Collino

Keyword(s):

Chronic Inflammation ◽

Nlrp3 Inflammasome ◽

Metabolic Disorders ◽

Inflammasome Activation ◽

Nucleotide Binding Domain ◽

Metabolic Inflammation ◽

Nlrp3 Inflammasome Activation ◽

Leucine Rich Repeat Protein

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1βand IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

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Coenzyme Q0 Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/4266214 ◽

2022 ◽

Vol 2022 ◽

pp. 1-15

Author(s):

You-Cheng Hseu ◽

Yu-Fang Tseng ◽

Sudhir Pandey ◽

Sirjana Shrestha ◽

Kai-Yuan Lin ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Coenzyme Q ◽

Antioxidant Properties ◽

Variable Number ◽

Ros Generation ◽

Inflammasome Activation ◽

Raw264.7 Macrophages ◽

Mitochondrial Ros ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammatory

Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-induced inflammation and redox imbalance in murine RAW264.7 macrophages. CoQ0’s non- or subcytotoxic concentration suppressed the NLRP3 inflammasome and procaspase-1 activation, followed by downregulation of IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages. Similarly, treatment of CoQ0 led to LC3-I/II accumulation and p62/SQSTM1 activation. An increase in the Beclin-1/Bcl-2 ratio and a decrease in the expression of phosphorylated PI3K/AKT, p70 S6 kinase, and mTOR showed that autophagy was activated. Besides, CoQ0 increased Parkin protein to recruit damaged mitochondria and induced mitophagy in LPS/ATP-stimulated RAW264.7 macrophages. CoQ0 inhibited LPS/ATP-stimulated ROS generation in RAW264.7 macrophages. Notably, when LPS/ATP-stimulated RAW264.7 macrophages were treated with CoQ0, Mito-TEMPO (a mitochondrial ROS inhibitor), or N-acetylcysteine (NAC, a ROS inhibitor), there was a significant reduction of LPS/ATP-stimulated NLRP3 inflammasome activation and IL1β expression. Interestingly, treatment with CoQ0 or Mito-TEMPO, but not NAC, significantly increased LPS/ATP-induced LC3-II accumulation indicating that mitophagy plays a key role in the regulation of CoQ0-inhibited NLRP3 inflammasome activation. Nrf2 knockdown significantly decreased IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ0 inhibited ROS-mediated NLRP3 inflammasome activation and IL1β expression was suppressed due to the Nrf2 activation. Hence, this study showed that CoQ0 might be a promising candidate for the therapeutics of inflammatory disorders due to its effective anti-inflammatory as well as antioxidant properties.

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Abstract 11852: Role of Lox-1 in Mitochondrial Dna Damage and NLRP3 Inflammasome Activation

Circulation ◽

10.1161/circ.130.suppl_2.11852 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Zufeng Ding ◽

Sadip Pant ◽

Abhishek Deshmukh ◽

Jawahar L Mehta

Keyword(s):

Dna Damage ◽

Mitochondrial Dna ◽

Nlrp3 Inflammasome ◽

Ros Generation ◽

Inflammasome Activation ◽

Mtdna Damage ◽

Mitochondrial Dna Damage ◽

Mitochondrial Ros ◽

Nlrp3 Inflammasome Activation

Objective: This study tested the hypothesis that mitochondrial DNA damage could trigger NLRP3 inflammasome activation during inflammation, and LOX-1 may play a critical role in this process. Methods and Results: We performed studies in cultured human THP1 macrophages exposed to ox-LDL or LPS,which are often used as inflammation stimuli in vitro . We examined and confirmed the increase in LOX-1 expression when cells were treated with ox-LDL or LPS. Parallel groups of cells were treated with LOX-1 Ab to bind LOX-1. In accordance with our previous studies in endothelial cells and smooth muscle cells, LOX-1 Ab markedly reduced ox-LDL- as well as LPS-stimulated LOX-1 expression. To assess mitochondrial ROS generation, MitoSOX™ Red mitochondrial superoxide indicator was used. Both fluorescence staining and flow cytometry analysis showed that LPS induced (more than ox-LDL) mitochondrial ROS generation. Pretreatment with LOX-1 Ab significantly attenuated mitochondrial ROS generation in response to ox-LDL or LPS. Then we observed mtDNA damage in THP1 cells exposed to ox-LDL or LPS. Importantly, pretreatment with LOX-1 Ab protected mtDNA from damage in response to both stimuli. This was also confirmed by q-PCR (mtDNA/nDNA ratio) analysis. Further, ox-LDL or LPS induced the expression of phos-NF-kB p65, caspase-1 p10 and p20, and cleaved proteins IL-1β and IL-18. Of note, NLRP3 inflammasome was activated in response to ox-LDL or LPS in a similar manner. Pretreatment of cells with LOX-1 Ab treatment blocked or significantly attenuated these inflammatory responses. Conclusions: These observations based on in vitro observations indicate that LOX-1 via ROS generation plays a key role in mtDNA damage which then leads to NLRP3 inflammasome activation during inflammation.

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