scholarly journals NLRP3 inflammasome in endothelial dysfunction

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Baochen Bai ◽  
Yanyan Yang ◽  
Qi Wang ◽  
Min Li ◽  
Chao Tian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Protein Complexes ◽  
Cell Damage ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Clinical Drugs

Abstract Inflammasomes are a class of cytosolic protein complexes. They act as cytosolic innate immune signal receptors to sense pathogens and initiate inflammatory responses under physiological and pathological conditions. The NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome is the most characteristic multimeric protein complex. Its activation triggers the cleavage of pro-interleukin (IL)-1β and pro-IL-18, which are mediated by caspase-1, and secretes mature forms of these mediators from cells to promote the further inflammatory process and oxidative stress. Simultaneously, cells undergo pro-inflammatory programmed cell death, termed pyroptosis. The danger signals for activating NLRP3 inflammasome are very extensive, especially reactive oxygen species (ROS), which act as an intermediate trigger to activate NLRP3 inflammasome, exacerbating subsequent inflammatory cascades and cell damage. Vascular endothelium at the site of inflammation is actively involved in the regulation of inflammation progression with important implications for cardiovascular homeostasis as a dynamically adaptable interface. Endothelial dysfunction is a hallmark and predictor for cardiovascular ailments or adverse cardiovascular events, such as coronary artery disease, diabetes mellitus, hypertension, and hypercholesterolemia. The loss of proper endothelial function may lead to tissue swelling, chronic inflammation, and the formation of thrombi. As such, elimination of endothelial cell inflammation or activation is of clinical relevance. In this review, we provided a comprehensive perspective on the pivotal role of NLRP3 inflammasome activation in aggravating oxidative stress and endothelial dysfunction and the possible underlying mechanisms. Furthermore, we highlighted the contribution of noncoding RNAs to NLRP3 inflammasome activation-associated endothelial dysfunction, and outlined potential clinical drugs targeting NLRP3 inflammasome involved in endothelial dysfunction. Collectively, this summary provides recent developments and perspectives on how NLRP3 inflammasome interferes with endothelial dysfunction and the potential research value of NLRP3 inflammasome as a potential mediator of endothelial dysfunction.

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 NLRP3 inflammasome signaling is activated by low-level lysosome disruption but inhibited by extensive lysosome disruption: roles for K+ efflux and Ca2+ influx

2016 ◽  
Vol 311 (1) ◽  
pp. C83-C100 ◽  
Author(s):  
Michael A. Katsnelson ◽  
Kristen M. Lozada-Soto ◽  
Hana M. Russo ◽  
Barbara A. Miller ◽  
George R. Dubyak
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Dominant Negative ◽  
Cell Physiology ◽  
Inflammasome Activation ◽  
Negative Effects ◽  
Murine Bone Marrow ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation

Nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) is a cytosolic protein that nucleates assembly of inflammasome signaling platforms, which facilitate caspase-1-mediated IL-1β release and other inflammatory responses in myeloid leukocytes. NLRP3 inflammasomes are assembled in response to multiple pathogen- or environmental stress-induced changes in basic cell physiology, including the destabilization of lysosome integrity and activation of K+-permeable channels/transporters in the plasma membrane (PM). However, the quantitative relationships between lysosome membrane permeabilization (LMP), induction of increased PM K+ permeability, and activation of NLRP3 signaling are incompletely characterized. We used Leu-Leu- O-methyl ester (LLME), a soluble lysosomotropic agent, to quantitatively track the kinetics and extent of LMP in relation to NLRP3 inflammasome signaling responses (ASC oligomerization, caspase-1 activation, IL-1β release) and PM cation fluxes in murine bone marrow-derived dendritic cells (BMDCs). Treatment of BMDCs with submillimolar (≤1 mM) LLME induced slower and partial increases in LMP that correlated with robust NLRP3 inflammasome activation and K+ efflux. In contrast, supramillimolar (≥2 mM) LLME elicited extremely rapid and complete collapse of lysosome integrity that was correlated with suppression of inflammasome signaling. Supramillimolar LLME also induced dominant negative effects on inflammasome activation by the canonical NLRP3 agonist nigericin; this inhibition correlated with an increase in NLRP3 ubiquitination. LMP elicited rapid BMDC death by both inflammasome-dependent pyroptosis and inflammasome-independent necrosis. LMP also triggered Ca2+ influx, which attenuated LLME-stimulated NLRP3 inflammasome signaling but potentiated LLME-induced necrosis. Taken together, these studies reveal a previously unappreciated signaling network that defines the coupling between LMP, changes in PM cation fluxes, cell death, and NLRP3 inflammasome activation.

scholarly journals NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis

2019 ◽  
Vol 20 (14) ◽  
pp. 3466 ◽  
Author(s):  
Francesca Bonomini ◽  
Mariane Dos Santos ◽  
Francisco Veríssimo Veronese ◽  
Rita Rezzani
Keyword(s):  
Oxidative Stress ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Morphological Alteration ◽  
Inflammasome Activation ◽  
Protective Effects ◽  
Nlrp3 Inflammasome Activation

Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). NLRP3 inflammasome activation is implicated in LN pathogenesis, suggesting its potential targets for LN treatment. Melatonin, an endogenous indoleamine, is considered an important multitasking molecule that has been reported to have anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-κB)-mediated inflammatory responses in vivo. This molecule has also protective effects against the activation of the inflammasomes and, in particular, the NLRP3 inflammasome. Thus, this work evaluated the effect of melatonin on morphological alteration and NLRP3 inflammasome activation in LN pristane mouse models. To evaluate the melatonin effects in these mice, we studied the renal cytoarchitecture by means of morphological analyses and immunohistochemical expression of specific markers related to oxidative stress, inflammation and inflammasome activation. Our results showed that melatonin attenuates pristane-induced LN through restoring of morphology and attenuation of oxidative stress and inflammation through a pathway that inhibited activation of NLRP3 inflammasome signaling. Our data clearly demonstrate that melatonin has protective activity on lupus nephritis in these mice that is highly associated with its effect on enhancing the Nrf2 antioxidant signaling pathway and decreasing renal NLRP3 inflammasome activation.

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

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
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.

scholarly journals Alda-1, an Activator of ALDH2, Protects Cardiac and Neurological Function Postresuscitation by Inhibiting Pyroptosis in Swine

2021 ◽  
Author(s):  
Mengyuan Diao ◽  
Jiefeng Xu ◽  
Jiangang Wang ◽  
Minhai Zhang ◽  
Chenghao Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Spontaneous Circulation ◽  
Neurological Dysfunction ◽  
Neurological Injury ◽  
Swine Model ◽  
Inflammasome Activation ◽  
Stress Injury ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation

Abstract PurposeThe enzyme aldehyde dehydrogenase 2 (ALDH2) has been shown to protect the heart and brain from oxidative stress injury, and this effect is related to the inhibition of pyroptosis. In the present study, we hypothesised that the ALDH2 activator N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide (Alda-1) would mitigate cardiac and neurological injury postresuscitation in a preclinical swine model of CA.MethodsFollowing 8 minutes of untreated ventricular fibrillation, and another 8 minutes of cardiopulmonary resuscitation (CPR), the swine randomly received either Alda-1 (0.88 mg/kg, n = 6) or saline (n=5) after restoration of spontaneous circulation (ROSC). Hemodynamic parameters and cardiac function were monitored, and serial blood samples were collected postresuscitation to detect biomarkers of cardiac and neurological injury. At 24 hours postresuscitation, first, neurological scores were evaluated, and then, the swine were sacrificed and pyroptosis-related proteins, proinflammatory cytokines, and oxidative stress were assessed in heart and brain samples.ResultsCardiac and neurological injury were significantly improved in the Alda-1 group compared with the CPR group postresuscitation. In addition, after treatment with Alda-1, the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, Gasdermin D (GSDMD), and proinflammatory cytokine levels were markedly suppressed. Moreover, 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA), indicators of oxidative stress, were also significantly inhibited after Alda-1 administration, which was accompanied by increased ALDH2 activity and protein expression.ConclusionAlda-1 improves cardiac and neurological dysfunction postresuscitation in a swine model of CA, at least partly by inhibiting oxidative stress-mediated NLRP3 inflammasome activation and pyroptosis.

scholarly journals SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pan Pan ◽  
Miaomiao Shen ◽  
Zhenyang Yu ◽  
Weiwei Ge ◽  
Keli Chen ◽  
...  
Keyword(s):  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Cultured Cells ◽  
Inflammatory Responses ◽  
Specific Inhibitor ◽  
Inflammasome Activation ◽  
N Protein ◽  
Distinct Mechanism ◽  
Nlrp3 Inflammasome Activation ◽  
Proinflammatory Responses

AbstractExcessive inflammatory responses induced upon SARS-CoV-2 infection are associated with severe symptoms of COVID-19. Inflammasomes activated in response to SARS-CoV-2 infection are also associated with COVID-19 severity. Here, we show a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. N protein facilitates maturation of proinflammatory cytokines and induces proinflammatory responses in cultured cells and mice. Mechanistically, N protein interacts directly with NLRP3 protein, promotes the binding of NLRP3 with ASC, and facilitates NLRP3 inflammasome assembly. More importantly, N protein aggravates lung injury, accelerates death in sepsis and acute inflammation mouse models, and promotes IL-1β and IL-6 activation in mice. Notably, N-induced lung injury and cytokine production are blocked by MCC950 (a specific inhibitor of NLRP3) and Ac-YVAD-cmk (an inhibitor of caspase-1). Therefore, this study reveals a distinct mechanism by which SARS-CoV-2 N protein promotes NLRP3 inflammasome activation and induces excessive inflammatory responses.

scholarly journals Growth differentiation factor 11 ameliorates experimental colitis by inhibiting NLRP3 inflammasome activation

2018 ◽  
Vol 315 (6) ◽  
pp. G909-G920 ◽  
Author(s):  
Lanju Wang ◽  
Yaohui Wang ◽  
Zhenfeng Wang ◽  
Yu Qi ◽  
Beibei Zong ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Inflammasome Activation ◽  
Acute Colitis ◽  
Pyrin Domain ◽  
Differentiation Factor ◽  
Nlrp3 Inflammasome Activation ◽  
Receptor Family

Growth differentiation factor 11 (GDF11) has an anti-inflammatory effect in the mouse model of atherosclerosis and Alzheimer's disease, but how GDF11 regulates intestinal inflammation during ulcerative colitis (UC) is poorly defined. The Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome is closely associated with intestinal inflammation because of its ability to increase IL-1β secretion. Our aim is to determine whether GDF11 has an effect on attenuating experimental colitis in mice. In this study, using a dextran sodium sulfate (DSS)-induced acute colitis mouse model, we reported that GDF11 treatment attenuated loss of body weight, the severity of the disease activity index, shortening of the colon, and histological changes in the colon. GDF11 remarkably suppressed IL-1β secretion and NLRP3 inflammasome activation in colon samples and RAW 264.7 cells, such as the levels of NLRP3 and activated caspase-1. Furthermore, we found that GDF11 inhibited NLRP3 inflammasome activation by downregulating the Toll-like receptor 4/NF-κB p65 pathway and reactive oxygen species production via the typical Smad2/3 pathway. Thus, our research shows that GDF11 alleviates DSS-induced colitis by inhibiting NLRP3 inflammasome activation, providing some basis for its potential use in the treatment of UC. NEW & NOTEWORTHY Here, we identify a new role for growth differentiation factor 11 (GDF11), which ameliorates dextran sodium sulfate-induced acute colitis. Meanwhile, we discover a new phenomenon of GDF11 inhibiting IL-1β secretion and Nod-like receptor family pyrin domain-1 containing 3 (NLRP3) inflammasome activation. These findings reveal that GDF11 is a new potential candidate for the treatment of ulcerative colitis patients with a hyperactive NLRP3 inflammasome.

Psidium guajava Flavonoids Prevent NLRP3 Inflammasome Activation and Alleviate the Pancreatic Fibrosis in a Chronic Pancreatitis Mouse Model

2021 ◽  
Vol 49 (08) ◽  
pp. 2001-2015
Author(s):  
Guixian Zhang ◽  
Liming Tang ◽  
Hongbin Liu ◽  
Dawei Liu ◽  
Manxue Wang ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Signaling Pathway ◽  
Nlrp3 Inflammasome ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Psidium Guajava ◽  
Pancreatic Fibrosis ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Chronic pancreatitis (CP) is a multifactorial, inflammatory syndrome characterized by acinar atrophy and fibrosis. Activation of NOD-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome is a central mediator of multiple chronic inflammatory responses and chronic fibrosis including pancreatic fibrosis in CP. The Psidium guajavaleaf is widely used in traditional medicine for the treatment of chronic inflammation, but the anti-inflammatory effect of Psidium guajavaleaf on CP has not yet been revealed. In this study, we investigated whether the extract of total flavonoids from Psidium guajava leaves (TFPGL) plays a therapeutic mechanism on CP through NLRP3 inflammasome signaling pathway in a mouse CP model. The H&E and acid-Sirius red staining indicted that TFPGL attenuated the inflammatory cell infiltration and fibrosis significantly. The results of immunohistological staining, western blot and RT-qPCR showed that the expressions of NLRP3 and caspase-1 were significantly increased in the CP model group, while TFPGL significantly decreased the NLRP3 and caspase-1 expression at both the gene and protein levels. Moreover, ELISA assay was used to examine the levels of NLRP3 inflammasome target genes, such as caspase-1, IL-1[Formula: see text] and IL-18. We found that TFPGL treatment decreased the expression of caspase-1, IL-1[Formula: see text] and IL-18, which is critical for the NLRP3 inflammasome signaling pathway and inflammation response significantly. These results demonstrated that TFPGL attenuated pancreatic inflammation and fibrosis via preventing NLRP3 inflammasome activation and TFPGL can be used as a potential therapeutic agent for CP.

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