NLRP3 Inflammasome activation in macrophages regulates systemic inflammation and severity during acute pancreatitis.

Abstract Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

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Hydrogen-Rich Saline Inhibits NLRP3 Inflammasome Activation and Attenuates Experimental Acute Pancreatitis in Mice

Mediators of Inflammation ◽

10.1155/2014/930894 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Jian-Dong Ren ◽

Jie Ma ◽

Jun Hou ◽

Wen-Jin Xiao ◽

Wei-Hua Jin ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Pancreatitis ◽

Nlrp3 Inflammasome ◽

Therapeutic Potential ◽

Animal Experiments ◽

Therapeutic Benefit ◽

Pancreatic Tissue ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation

Increasing evidence has demonstrated that reactive oxygen species (ROS) induces oxidative stress and plays a crucial role in the pathogenesis of acute pancreatitis (AP). Hydrogen-rich saline (HRS), a well-known ROS scavenger, has been shown to possess therapeutic benefit on AP in many animal experiments. Recent findings have indicated that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, an intracellular multiprotein complex required for the maturation of interleukin- (IL-) 1β, may probably be a potential target of HRS in the treatment of AP. Therefore, in this study, we evaluated the activation of NLRP3 inflammasome and meanwhile assessed the degree of oxidative stress and inflammatory cascades, as well as the histological alterations in mice suffering from cerulein-induced AP after the treatment of HRS. The results showed that the activation of NLRP3 inflammasome in AP mice was substantially inhibited following the administration of HRS, which was paralleled with the decreased NF-κB activity and cytokines production, attenuated oxidative stress and the amelioration of pancreatic tissue damage. In conclusion, our study has, for the first time, revealed that inhibition of the activation of NLRP3 inflammasome probably contributed to the therapeutic potential of HRS in AP.

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Resveratrol reduces cardiac NLRP3‐inflammasome activation and systemic inflammation to lessen doxorubicin‐induced cardiotoxicity in juvenile mice

FEBS Letters ◽

10.1002/1873-3468.14091 ◽

2021 ◽

Author(s):

Zaid H. Maayah ◽

Abrar S. Alam ◽

Shingo Takahara ◽

Shubham Soni ◽

Mourad Ferdaoussi ◽

...

Keyword(s):

Systemic Inflammation ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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Surfactant Protein D Dampens Lung Injury by Suppressing NLRP3 Inflammasome Activation and NF-κB Signaling in Acute Pancreatitis

Shock ◽

10.1097/shk.0000000000001244 ◽

2019 ◽

Vol 51 (5) ◽

pp. 557-568 ◽

Cited By ~ 11

Author(s):

Jia Yu ◽

Lan Ni ◽

Xiaoyi Zhang ◽

Jing Zhang ◽

Osama Abdel-Razek ◽

...

Keyword(s):

Acute Pancreatitis ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Surfactant Protein ◽

Surfactant Protein D ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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Cordycepin protects against acute pancreatitis by modulating NF-κB and NLRP3 inflammasome activation via AMPK

Life Sciences ◽

10.1016/j.lfs.2020.117645 ◽

2020 ◽

Vol 251 ◽

pp. 117645 ◽

Cited By ~ 3

Author(s):

Jing Yang ◽

Yiwen Zhou ◽

Jinsong Shi

Keyword(s):

Acute Pancreatitis ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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NLRP3 Inflammasome-Mediated Inflammation in Acute Pancreatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21155386 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5386 ◽

Cited By ~ 1

Author(s):

Ana Ferrero-Andrés ◽

Arnau Panisello-Roselló ◽

Joan Roselló-Catafau ◽

Emma Folch-Puy

Keyword(s):

Acute Pancreatitis ◽

Nlrp3 Inflammasome ◽

Inflammatory Diseases ◽

Interleukin 1 ◽

Pancreatic Injury ◽

Inflammasome Activation ◽

Inflammatory Disorder ◽

Pyrin Domain ◽

Current State ◽

Nlrp3 Inflammasome Activation

The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.

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AICAR, an AMP-Activated Protein Kinase Activator, Ameliorates Acute Pancreatitis-Associated Liver Injury Partially Through Nrf2-Mediated Antioxidant Effects and Inhibition of NLRP3 Inflammasome Activation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.724514 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lijun Kong ◽

Hewei Zhang ◽

Chaosheng Lu ◽

Keqing Shi ◽

Hongjian Huang ◽

...

Keyword(s):

Acute Pancreatitis ◽

Protein Kinase ◽

Liver Injury ◽

Nlrp3 Inflammasome ◽

Sodium Taurocholate ◽

Inflammasome Activation ◽

Ampk Activation ◽

Compound C ◽

Nlrp3 Inflammasome Activation ◽

Antioxidant Effects

Acute pancreatitis (AP) is a highly fatal acute inflammation and is often accompanied by multiple organ dysfunction syndrome (MODS). The liver, one of the most vulnerable extrapancreatic organs in AP, is the major organ involved in the evolution of the disease and correlates strongly with the occurrence of MODS. However, the etiology of pancreatitis-associated liver injury (PALI) has not been clarified and currently lacks an effective treatment. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is a cell permeable nucleoside with pleiotropic effects on anti-inflammatory and antioxidant stress that binds with adenosine monophosphate protein kinase (AMPK) and induces AMPK activation. However, the role of AICAR in PALI remains elusive. Here, we show that activation of AMPK by AICAR, a direct AMPK agonist, significantly ameliorates sodium taurocholate-induced PALI in rats, whereas treatment of PALI rats with the AMPK antagonist Compound C profoundly exacerbates the degree of liver injury, suggesting that hepatic AMPK activation exerts an essential protective role in PALI. Mechanistically, AICAR induces AMPK activation, which in turn activates nuclear factor erythroid 2-related factor 2(Nrf2) -regulated hepatic antioxidant capacity and inhibits NLRP3 inflammasome-mediated pyrolysis, protecting rats from sodium taurocholate-induced PALI. In addition, Nrf2 deficiency strikingly weakens the beneficial effects of AICAR on alleviation of liver injury, oxidative stress and NLRP3 inflammasome activation in L-arginine-induced PALI mice. Thus, AICAR protects against PALI in rodents by triggering AMPK, which is mediated at least in part by Nrf2-modulated antioxidant effects and NLRP3 inflammasome activation.

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