scholarly journals NLRP3 Inflammasome at the Interface of Inflammation, Endothelial Dysfunction, and Type 2 Diabetes

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 314
Author(s):  
Ilona M. Gora ◽  
Anna Ciechanowska ◽  
Piotr Ladyzynski
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Vascular Complications ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Pro Inflammatory Cytokines

Type 2 diabetes mellitus (T2DM), accounting for 90–95% cases of diabetes, is characterized by chronic inflammation. The mechanisms that control inflammation activation in T2DM are largely unexplored. Inflammasomes represent significant sensors mediating innate immune responses. The aim of this work is to present a review of links between the NLRP3 inflammasome, endothelial dysfunction, and T2DM. The NLRP3 inflammasome activates caspase-1, which leads to the maturation of pro-inflammatory cytokines interleukin 1β and interleukin 18. In this review, we characterize the structure and functions of NLRP3 inflammasome as well as the most important mechanisms and molecules engaged in its activation. We present evidence of the importance of the endothelial dysfunction as the first key step to activating the inflammasome, which suggests that suppressing the NLRP3 inflammasome could be a new approach in depletion hyperglycemic toxicity and in averting the onset of vascular complications in T2DM. We also demonstrate reports showing that the expression of a few microRNAs that are also known to be involved in either NLRP3 inflammasome activation or endothelial dysfunction is deregulated in T2DM. Collectively, this evidence suggests that T2DM is an inflammatory disease stimulated by pro-inflammatory cytokines. Finally, studies revealing the role of glucose concentration in the activation of NLRP3 inflammasome are analyzed. The more that is known about inflammasomes, the higher the chances to create new, effective therapies for patients suffering from inflammatory diseases. This may offer potential novel therapeutic perspectives in T2DM prevention and treatment.

scholarly journals Fucoxanthin from microalgae Phaeodactylum tricornutum inhibits pro-inflammatory cytokines by regulating both NF-κB and NLRP3 inflammasome activation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A-Hyeon Lee ◽  
Hye-Yoon Shin ◽  
Jong-Hwi Park ◽  
Song Yi Koo ◽  
Sang Min Kim ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Phaeodactylum Tricornutum ◽  
Inflammatory Diseases ◽  
Inhibitory Effect ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α ◽  
Main Components ◽  
Pro Inflammatory Cytokines

AbstractPro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are mediated by the activation of various kinds of signaling pathways in the innate immune system. Particularly, NF-κB and NLRP3 inflammasome signaling are involved in the production and secretion of these cytokines. Each signaling is participated in the two steps necessary for IL-1β, a representative pro-inflammatory cytokine, to be processed into a form secreted by cells. In the priming step stimulated by LPS, pro-IL-1β is synthesized through NF-κB activation. Pro-IL-1β cleavages into mature IL-1β by formed NLRP3 inflammasome in the activation step induced by ATP. The mature form of IL-1β is subsequently secreted out of the cell, causing inflammation. Moreover, IL-6 and TNF-α are known to increase in NLRP3 inflammasome-mediated conditions. Here, we found that fucoxanthin, one of the major components of Phaeodactylum tricornutum, has an inhibitory effect on NF-κB and NLRP3 inflammasome activation induced by the combination of LPS and ATP in bone marrow-derived immune cells as well as astrocytes. Fucoxanthin, which is abundant in the EtOH fraction of Phaeodactylum tricornutum extracts, has shown to have less cell toxicity and found to decrease the production of major pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Fucoxanthin has also shown to suppress the expression of cleaved caspase-1 and the oligomerization of ASC, which are the main components of the NLRP3 inflammasome. Furthermore, phosphorylated IκBα and pro-IL-1β expression decreased in the presence of fucoxanthin, suggesting that fucoxanthin can negatively regulate the priming step of inflammasome signaling. Thus, our results provide reliable evidence that fucoxanthin may serve as a key candidate in the development of potential therapeutic agents for inflammatory diseases as well as neurodegenerative diseases caused by NF-κB and NLRP3 inflammasome activation.

Abstract P632: Nlrp3/inflammasome Activation Contributes To Aldosterone-induced Vascular Dysfunction In Type 2 Diabetes.

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nathanne S Ferreira ◽  
Thiago Bruder-Nascimento ◽  
Camila A Pereira ◽  
Camila Z Zanotto ◽  
Douglas S Prado ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Diabetic Patients ◽  
Inflammasome Activation ◽  
Caspase 1

Diabetic patients and animal models of type 2 diabetes (DM2) display increased plasma aldosterone (aldo) levels. Aldo induces vascular inflammation and endothelial dysfunction. NOD-like receptors, which are pattern recognition receptors involved in a variety of host innate immune responses, promote vascular inflammation. We hypothesized that aldo via mineralocorticoid receptors (MR) activates the inflammasome platform in the vasculature of DM2 mice. Control (db/+) and diabetic (db/db) mice were treated with vehicle or spironolactone (spiro - MR antagonist, 50 mg/Kg/day). Mesenteric resistance arteries (MA) from db/db mice exhibited reduced acetylcholine (ACh) dilation, which was reversed by spiro [Emax (% of relaxation): db/+: 78.5±4.1; db/db: 40.5±6.4; db/+spiro: 77.0±3.8; db/db+spiro: 62.8±5.9 n=3-6 p<0.05]. Spiro treatment reduced caspase-1 and mature IL-1β content in MA from db/db mice. Spiro also reduced caspase-1 activity in macrophages from peritoneal lavage of db/db mice [% of activity: db/+: 33.9±2.5; db/db: 51.8±7.4; db/+spiro: 31.1±1.9; db/db+spiro: 34.8±3.8 n=4-7, p<0.05]. In vitro, aldo increased mature IL-1β in vascular smooth muscle cells (VSMC) (cont: 0.9±0.01 ; LPS+Nigericine: 6.1±2.1 ; Aldo 4h: 9.7±2.6; LPS+Aldo 4h: 12.8±1.9 n=3-5, p<0.05). To determine whether aldo in vivo directly activates NLRP3/inflammasome in the vasculature and whether NLRP3 activation contributes to aldo-induced vascular injury, aldo was infused (600 ug/Kg/day for 14 days) in wild type (WT) and NLRP3 knockout mice ( NLRP3-/- ) after bone marrow transplantation from WT donor. The groups were constituted: WT->WT, WT->WT+aldo and WT-> NLRP3 -/-+aldo. NLRP3 -/- mice were protected against aldo-induced endothelial dysfunction [Emax: WT: 89.3±2.9; WT+aldo: 39.8±1.8; NLRP3-/- +aldo: 87.7±4.2, p<0.05]. Aldo treatment leaded to endothelial dysfunction in WT ->WT mice, but WT-> NLRP3 -/- mice were protected from aldo-induced endothelial dysfunction [Emax: WT->WT: 95.1±3.1; WT->WT+aldo: 57.1±4.7; WT->NLRP3-/-+aldo: 85.3±3.1 p<0.05]. These results suggest that NLRP3/inflammasome in the vasculature plays a crucial role on aldo/MR-induced vascular damage and on DM2-associated vascular dysfunction. Financial Support: FAPESP, CAPES, CNPq.

Does Glycemic Control Modulate the Impairment of NLRP3 Inflammasome Activation in Type 2 Diabetes?

2019 ◽  
Vol 30 (2) ◽  
pp. 232-240 ◽  
Author(s):  
Francesca Iannantuoni ◽  
Noelia Diaz-Morales ◽  
Irene Escribano-Lopez ◽  
Eva Sola ◽  
Ildefonso Roldan-Torres ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glycemic Control ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

P6294NLRP3 inflammasome is activated in the atrium of an ovine model of sustained obesity

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Saljic ◽  
M Hohl ◽  
N Li ◽  
T Agbaedeng ◽  
D Twomey ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Fat Infiltration ◽  
Protein Levels ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Arrhythmogenic Substrate ◽  
Pro Inflammatory Cytokines

Abstract Introduction Obesity and enhanced inflammatory response are two independent risk factors involved in the pathogenesis of atrial fibrillation (AF). Components of the NLRP3 inflammasome have been found to be expressed in cardiomyocytes and cardiac fibroblasts and that increased inflammasome activation contributes to the pathogenesis of AF. The NLRP3 inflammasome is a multi-protein signaling complex that is activated in two steps: 1st) a priming event that includes a NFκB-activating stimuli which increases the expression of pro-inflammatory cytokines, and 2nd) a triggering event that includes the assembly of the inflammasome complex and activation of caspase-1 which promotes the production of pro-inflammatory cytokines like interleukin 1 beta (IL-1b). Purpose We used a sheep model of sustained obesity to characterize the association between atrial myocardial fat infiltration, atrial activation of the NLRP3 inflammasome and the development of an atrial arrhythmogenic substrate for AF. Methods Eight sheep were fed ad libitum calorie-dense diet over 40 weeks to gain weight and were maintained in this state of sustained obesity for another 40 weeks. Eight lean, weight-controlled and aged-matched sheep served as control. Atrial fat infiltration was determined by oil-red staining and NLRP3 inflammasome activation was assessed by immunoblot in atrial whole-tissue lysate. Atrial effective refractory periods (aERPs) were evaluated (twice diastolic threshold, cycle length (CL) of 400 ms, S1S2 -protocol). Results Sustained obesity was associated with increased atrial fat infiltration (lean: 0.8±0.3% vs. obese: 2.3±1.2%, p=0.1) and shorter aERP (lean: 169±22ms vs. obese: 138±26ms, p=0.03). Protein levels of caspase-1 and mature IL-1β were significantly enhanced (p=0.04 and p=0.01, respectively). Further shortening of aERP correlated with increasing atrial protein levels of caspase-1 (r=0.59, p=0.02). In contrast, levels of TNFα and NFκB were not significantly changed in atria of sheep with sustained obesity. Conclusions Sustained obesity is associated with increased expression of NLRP3 inflammasome-related proteins and the development of an arrhythmogenic substrate for AF. Our study suggest that the increased activity is due to increased triggering, rather than increased gene transcription. Whether NLRP3 inflammasome activation represents a modifiable target to prevent AF in obesity warrants further study.

scholarly journals NLRP3 inflammasome-mediated cytokine production and pyroptosis cell death in breast cancer

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Sara Socorro Faria ◽  
Susan Costantini ◽  
Vladmir Cláudio Cordeiro de Lima ◽  
Victor Pianna de Andrade ◽  
Mickaël Rialland ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Chronic Inflammation ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Metastatic Potential ◽  
Inflammasome Activation ◽  
Novel Therapeutic Strategies ◽  
Pro Inflammatory Cytokines

AbstractBreast cancer is the most diagnosed malignancy in women. Increasing evidence has highlighted the importance of chronic inflammation at the local and/or systemic level in breast cancer pathobiology, influencing its progression, metastatic potential and therapeutic outcome by altering the tumor immune microenvironment. These processes are mediated by a variety of cytokines, chemokines and growth factors that exert their biological functions either locally or distantly. Inflammasomes are protein signaling complexes that form in response to damage- and pathogen-associated molecular patterns (DAMPS and PAMPS), triggering the release of pro-inflammatory cytokines. The dysregulation of inflammasome activation can lead to the development of inflammatory diseases, neurodegeneration, and cancer. A crucial signaling pathway leading to acute and chronic inflammation occurs through the activation of NLRP3 inflammasome followed by caspase 1-dependent release of IL-1β and IL-18 pro-inflammatory cytokines, as well as, by gasdermin D-mediated pyroptotic cell death. In this review we focus on the role of NLRP3 inflammasome and its components in breast cancer signaling, highlighting that a more detailed understanding of the clinical relevance of these pathways could significantly contribute to the development of novel therapeutic strategies for breast cancer.

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 ◽  
Marina Saresella ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Beclin 1 ◽  
Inflammasome Activation ◽  
Beneficial Effects ◽  
Nlrp3 Inflammasome Activation ◽  
Chaperone Mediated Autophagy ◽  
Nlrp3 Activity ◽  
Pro Inflammatory Cytokines

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.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 activity by measuring NLRP3-ASC complexes formation by AMNIS Flow-sight and pro-inflammatory cytokines (IL-1β, IL-18 and Caspase-1) production by 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 pro-inflammatory 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.

scholarly journals Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes

Diabetes ◽  
2012 ◽  
Vol 62 (1) ◽  
pp. 194-204 ◽  
Author(s):  
Hye-Mi Lee ◽  
Jwa-Jin Kim ◽  
Hyun Jin Kim ◽  
Minho Shong ◽  
Bon Jeong Ku ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation
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