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The Role of NLRP3 in Health and Disease
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The Role of NLRP3 in Health and Disease

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cell Signaling".

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Editor

Prof. Dr. Alexander Wree

E-Mail Website1 Website2
Collection Editor
Department of Hepatology and Gastroenterology, Campus Virchow Klinikum and Campus Charité Mitte, Charité University Medicine Berlin, 13353 Berlin, Germany
Interests: NLRP3 signaling in acute and chronic inflammatory liver diseases; identification of novel prognostic biomarkers in gastrohepatic diseases

Topical Collection Information

Dear Colleagues, 

NLRP3 inflammasome activation and its downstream signaling has been shown to be involved in the development and progression of various inflammatory diseases, including NASH, fibrosis, inflammatory bowel diseases, rheumatoid arthritis, neurodegenerative disorders, metabolic, cardiovascular, as well as pulmonary diseases. 

As crucial regulators of inflammation and cell fate, the NLRP3 inflammasomes sense a wide range of danger signals by NOD‐like receptors provoking caspase-1 activation, IL-1β and IL-18 processing and release, as well as the initiation of pyroptosis, a novel form of programmed cell death. NLRP3 dysregulation or hyperactivation result in a spectrum of rare autosomal dominant diseases summarized as cryopyrin-associated periodic fever syndromes. Although recent studies have improved our understanding of inflammasome activation and signaling, several aspects of the NLRP3 inflammasome are not characterized yet or remain unclear. 

In this Topical Collection of the journal Cells, I would like to invite you to contribute original research articles, reviews or shorter perspective articles on all aspects related to the theme of “The Role of NLRP3 in Health and Disease”. Expert articles describing mechanistic, functional, cellular, biochemical or general aspects of NLRP3 activation and signaling are highly welcome.

Prof. Dr. Alexander Wree
Collection Editor

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Keywords

  • Inflammation
  • Innate immunity
  • Inflammasomes
  • NLRP3-mediated signaling pathways and diseases
  • Liver diseases
  • Cardiovascular diseases
  • Gut-liver axis
  • Cancer
  • Therapeutic targets

Published Papers (12 papers)

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2023

Jump to: 2022, 2021

31 pages, 1791 KiB  
Review
Inflammasomes: Mechanisms of Action and Involvement in Human Diseases
by Dimitri Bulté, Chiara Rigamonti, Alessandro Romano and Alessandra Mortellaro
Cells 2023, 12(13), 1766; https://doi.org/10.3390/cells12131766 - 03 Jul 2023
Cited by 11 | Viewed by 3134
Abstract
Inflammasome complexes and their integral receptor proteins have essential roles in regulating the innate immune response and inflammation at the post-translational level. Yet despite their protective role, aberrant activation of inflammasome proteins and gain of function mutations in inflammasome component genes seem to [...] Read more.
Inflammasome complexes and their integral receptor proteins have essential roles in regulating the innate immune response and inflammation at the post-translational level. Yet despite their protective role, aberrant activation of inflammasome proteins and gain of function mutations in inflammasome component genes seem to contribute to the development and progression of human autoimmune and autoinflammatory diseases. In the past decade, our understanding of inflammasome biology and activation mechanisms has greatly progressed. We therefore provide an up-to-date overview of the various inflammasomes and their known mechanisms of action. In addition, we highlight the involvement of various inflammasomes and their pathogenic mechanisms in common autoinflammatory, autoimmune and neurodegenerative diseases, including atherosclerosis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. We conclude by speculating on the future avenues of research needed to better understand the roles of inflammasomes in health and disease. Full article
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2022

Jump to: 2023, 2021

25 pages, 5748 KiB  
Article
The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction
by Irvan Alfian, Amlan Chakraborty, Hannah E. J. Yong, Sheetal Saini, Ricky W. K. Lau, Bill Kalionis, Evdokia Dimitriadis, Nadia Alfaidy, Sharon D. Ricardo, Chrishan S. Samuel and Padma Murthi
Cells 2022, 11(9), 1413; https://doi.org/10.3390/cells11091413 - 21 Apr 2022
Cited by 11 | Viewed by 4613
Abstract
Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene [...] Read more.
Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (<2-fold) in FGR compared with control pregnancies. LPS treatment increased NLRP3 and caspase-1 expression (>2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR. Full article
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21 pages, 1844 KiB  
Review
Specific NLRP3 Inflammasome Assembling and Regulation in Neutrophils: Relevance in Inflammatory and Infectious Diseases
by Christophe Paget, Emilie Doz-Deblauwe, Nathalie Winter and Benoit Briard
Cells 2022, 11(7), 1188; https://doi.org/10.3390/cells11071188 - 01 Apr 2022
Cited by 24 | Viewed by 7507
Abstract
The NLRP3 inflammasome is a cytosolic multimeric protein platform that leads to the activation of the protease zymogen, caspase-1 (CASP1). Inflammasome activation mediates the proteolytic activation of pro-inflammatory cytokines (IL-1β and IL-18) and program cell death called pyroptosis. The pyroptosis is mediated by [...] Read more.
The NLRP3 inflammasome is a cytosolic multimeric protein platform that leads to the activation of the protease zymogen, caspase-1 (CASP1). Inflammasome activation mediates the proteolytic activation of pro-inflammatory cytokines (IL-1β and IL-18) and program cell death called pyroptosis. The pyroptosis is mediated by the protein executioner Gasdermin D (GSDMD), which forms pores at the plasma membrane to facilitate IL-1β/IL-18 secretion and causes pyroptosis. The NLRP3 inflammasome is activated in response to a large number of pathogenic and sterile insults. However, an uncontrolled inflammasome activation may drive inflammation-associated diseases. Initially, inflammasome-competent cells were believed to be limited to macrophages, dendritic cells (DC), and monocytes. However, emerging evidence indicates that neutrophils can assemble inflammasomes in response to various stimuli with functional relevance. Interestingly, the regulation of inflammasome in neutrophils appears to be unconventional. This review provides a broad overview of the role and regulation of inflammasomes—and more specifically NLRP3—in neutrophils. Full article
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2021

Jump to: 2023, 2022

15 pages, 1897 KiB  
Article
Human Renal Fibroblasts, but Not Renal Epithelial Cells, Induce IL-1β Release during a Uropathogenic Escherichia coli Infection In Vitro
by Ashok Kumar Kumawat, Geena Varghese Paramel, Kartheyaene Jayaprakash Demirel and Isak Demirel
Cells 2021, 10(12), 3522; https://doi.org/10.3390/cells10123522 - 13 Dec 2021
Cited by 1 | Viewed by 2212
Abstract
Understanding how uropathogenic Escherichia coli (UPEC) modulates the immune response in the kidney is essential to prevent UPEC from reaching the bloodstream and causing urosepsis. The purpose of this study was to elucidate if renal fibroblasts can release IL-1β during a UPEC infection [...] Read more.
Understanding how uropathogenic Escherichia coli (UPEC) modulates the immune response in the kidney is essential to prevent UPEC from reaching the bloodstream and causing urosepsis. The purpose of this study was to elucidate if renal fibroblasts can release IL-1β during a UPEC infection and to investigate the mechanism behind the IL-1β release. We found that the UPEC strain CFT073 induced an increased IL-1β and LDH release from renal fibroblasts, but not from renal epithelial cells. The UPEC-induced IL-1β release was found to be NLRP3, caspase-1, caspase-4, ERK 1/2, cathepsin B and serine protease dependent in renal fibroblasts. We also found that the UPEC virulence factor α-hemolysin was necessary for IL-1β release. Conditioned medium from caspase-1, caspase-4 and NLRP3-deficient renal fibroblasts mediated an increased reactive oxygen species production from neutrophils, but reduced UPEC phagocytosis. Taken together, our study demonstrates that renal fibroblasts, but not renal epithelial cells, release IL-1β during a UPEC infection. This suggest that renal fibroblasts are vital immunoreactive cells and not only structural cells that produce and regulate the extracellular matrix. Full article
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26 pages, 37139 KiB  
Review
Walking down Skeletal Muscle Lane: From Inflammasome to Disease
by Nicolas Dubuisson, Romain Versele, María A. Davis-López de Carrizosa, Camille M. Selvais, Sonia M. Brichard and Michel Abou-Samra
Cells 2021, 10(11), 3023; https://doi.org/10.3390/cells10113023 - 04 Nov 2021
Cited by 14 | Viewed by 3850
Abstract
Over the last decade, innate immune system receptors and sensors called inflammasomes have been identified to play key pathological roles in the development and progression of numerous diseases. Among them, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-) and pyrin domain-containing protein 3 [...] Read more.
Over the last decade, innate immune system receptors and sensors called inflammasomes have been identified to play key pathological roles in the development and progression of numerous diseases. Among them, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-) and pyrin domain-containing protein 3 (NLRP3) inflammasome is probably the best characterized. To date, NLRP3 has been extensively studied in the heart, where its effects and actions have been broadly documented in numerous cardiovascular diseases. However, little is still known about NLRP3 implications in muscle disorders affecting non-cardiac muscles. In this review, we summarize and present the current knowledge regarding the function of NLRP3 in diseased skeletal muscle, and discuss the potential therapeutic options targeting the NLRP3 inflammasome in muscle disorders. Full article
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16 pages, 262893 KiB  
Article
Instructions for Flow Cytometric Detection of ASC Specks as a Readout of Inflammasome Activation in Human Blood
by Nico Wittmann, Ann-Kathrin Behrendt, Neha Mishra, Lukas Bossaller and Almut Meyer-Bahlburg
Cells 2021, 10(11), 2880; https://doi.org/10.3390/cells10112880 - 26 Oct 2021
Cited by 4 | Viewed by 3764
Abstract
Inflammasome activation is linked to the aggregation of the adaptor protein ASC into a multiprotein complex, known as the ASC speck. Redistribution of cytosolic ASC to this complex has been widely used as a readout for inflammasome activation and precedes the downstream proteolytic [...] Read more.
Inflammasome activation is linked to the aggregation of the adaptor protein ASC into a multiprotein complex, known as the ASC speck. Redistribution of cytosolic ASC to this complex has been widely used as a readout for inflammasome activation and precedes the downstream proteolytic release of the proinflammatory cytokines, IL-1β and IL-18. Although inflammasomes are important for many diseases such as periodic fever syndromes, COVID-19, gout, sepsis, atherosclerosis and Alzheimer’s disease, only a little knowledge exists on the precise and cell type specific occurrence of inflammasome activation in patient samples ex vivo. In this report, we provide detailed information about the optimal conditions to reliably identify inflammasome activated monocytes by ASC speck formation using a modified flow cytometric method introduced by Sester et al. in 2015. Since no protocol for optimal sample processing exists, we tested human blood samples for various conditions including anticoagulant, time and temperature, the effect of one freeze–thaw cycle for PBMC storage, and the fast generation of a positive control. We believe that this flow cytometric protocol will help researchers to perform high quality translational research in multicenter studies, and therefore provide a basis for investigating the role of the inflammasome in the pathogenesis of various diseases. Full article
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18 pages, 8599 KiB  
Article
Bile Acids Activate NLRP3 Inflammasome, Promoting Murine Liver Inflammation or Fibrosis in a Cell Type-Specific Manner
by Theresa Maria Holtmann, Maria Eugenia Inzaugarat, Jana Knorr, Lukas Geisler, Marten Schulz, Veerle Bieghs, Mick Frissen, Ariel E. Feldstein, Frank Tacke, Christian Trautwein and Alexander Wree
Cells 2021, 10(10), 2618; https://doi.org/10.3390/cells10102618 - 01 Oct 2021
Cited by 19 | Viewed by 3140
Abstract
Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of [...] Read more.
Bile acids (BA) as important signaling molecules are considered crucial in development of cholestatic liver injury, but there is limited understanding on the involved cell types and signaling pathways. The aim of this study was to evaluate the inflammatory and fibrotic potential of key BA and the role of distinct liver cell subsets focusing on the NLRP3 inflammasome. C57BL/6 wild-type (WT) and Nlrp3−/− mice were fed with a diet supplemented with cholic (CA), deoxycholic (DCA) or lithocholic acid (LCA) for 7 days. Additionally, primary hepatocytes, Kupffer cells (KC) and hepatic stellate cells (HSC) from WT and Nlrp3−/− mice were stimulated with aforementioned BA ex vivo. LCA feeding led to strong liver damage and activation of NLRP3 inflammasome. Ex vivo KC were the most affected cells by LCA, resulting in a pro-inflammatory phenotype. Liver damage and primary KC activation was both ameliorated in Nlrp3-deficient mice or cells. DCA feeding induced fibrotic alterations. Primary HSC upregulated the NLRP3 inflammasome and early fibrotic markers when stimulated with DCA, but not LCA. Pro-fibrogenic signals in liver and primary HSC were attenuated in Nlrp3−/− mice or cells. The data shows that distinct BA induce NLRP3 inflammasome activation in HSC or KC, promoting fibrosis or inflammation. Full article
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14 pages, 2886 KiB  
Article
Sinapic Acid Controls Inflammation by Suppressing NLRP3 Inflammasome Activation
by Eun Hye Lee, Jin Hak Shin, Seon Sook Kim and Su Ryeon Seo
Cells 2021, 10(9), 2327; https://doi.org/10.3390/cells10092327 - 06 Sep 2021
Cited by 21 | Viewed by 2809
Abstract
A natural phenolic acid compound, sinapic acid (SA), is a cinnamic acid derivative that contains 3,5-dimethoxyl and 4-hydroxyl substitutions in the phenyl ring of cinnamic acid. SA is present in various orally edible natural herbs and cereals and is reported to have antioxidant, [...] Read more.
A natural phenolic acid compound, sinapic acid (SA), is a cinnamic acid derivative that contains 3,5-dimethoxyl and 4-hydroxyl substitutions in the phenyl ring of cinnamic acid. SA is present in various orally edible natural herbs and cereals and is reported to have antioxidant, antitumor, anti-inflammatory, antibacterial, and neuroprotective activities. Although the anti-inflammatory function of SA has been reported, the effect of SA on the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome has not been explored. In the present study, to elucidate the anti-inflammatory mechanism of SA, we examined whether SA modulates the NLRP3 inflammasome. We found that SA blocked caspase-1 activation and IL-1β secretion by inhibiting NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs). Apoptosis-associated speck-like protein containing CARD (ASC) pyroptosome formation was consistently blocked by SA treatment. SA specifically inhibited NLRP3 activation but not the NLRC4 or AIM2 inflammasomes. In addition, SA had no significant effect on the priming phase of the NLRP3 inflammasome, such as pro-IL-1β and NLRP3 inflammasome expression levels. Moreover, we found that SA attenuated IL-1β secretion in LPS-induced systemic inflammation in mice and reduced lethality from endotoxic shock. Our findings suggest that the natural compound SA has potential therapeutic value for the suppression of NLRP3 inflammasome-associated inflammatory diseases. Full article
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22 pages, 1084 KiB  
Review
Inflammasomes and Colorectal Cancer
by Sanaz Keshavarz Shahbaz, Khadijeh Koushki, Seyed Hassan Ayati, Abigail R. Bland, Evgeny E. Bezsonov and Amirhossein Sahebkar
Cells 2021, 10(9), 2172; https://doi.org/10.3390/cells10092172 - 24 Aug 2021
Cited by 19 | Viewed by 2838
Abstract
Inflammasomes are important intracellular multiprotein signaling complexes that modulate the activation of caspase-1 and induce levels of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 in response to pathogenic microorganisms and molecules that originated from host proteins. Inflammasomes play contradictory roles in the development [...] Read more.
Inflammasomes are important intracellular multiprotein signaling complexes that modulate the activation of caspase-1 and induce levels of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 in response to pathogenic microorganisms and molecules that originated from host proteins. Inflammasomes play contradictory roles in the development of inflammation-induced cancers. Based on several findings, inflammasomes can initiate and promote carcinogenesis. On the contrary, inflammasomes also exhibit anticancer effects by triggering pyroptosis and immunoregulatory functions. Herein, we review extant studies delving into different functions of inflammasomes in colorectal cancer development. Full article
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10 pages, 2380 KiB  
Article
NLRP3 Triggers Attenuate Lipocalin-2 Expression Independent with Inflammasome Activation
by Huijeong Ahn, Gilyoung Lee, Jeongeun Kim, Jeongho Park, Seung Goo Kang, Sung-Il Yoon, Eunsong Lee and Geun-Shik Lee
Cells 2021, 10(7), 1660; https://doi.org/10.3390/cells10071660 - 02 Jul 2021
Cited by 6 | Viewed by 2553
Abstract
Lipocalin-2 (LCN2), a small secretory glycoprotein, is upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 inhibits bacterial growth by iron sequestration and regulates the innate immune system. Inflammasome activates the inflammatory caspases leading to pyroptosis and cytokine maturation. This [...] Read more.
Lipocalin-2 (LCN2), a small secretory glycoprotein, is upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 inhibits bacterial growth by iron sequestration and regulates the innate immune system. Inflammasome activates the inflammatory caspases leading to pyroptosis and cytokine maturation. This study examined the effects of inflammasome activation on LCN2 secretion in response to TLR signaling. The triggers of NLRP3 inflammasome activation attenuated LCN2 secretion while it induced interleukin-1β in mouse macrophages. In mice, NLRP3 inflammasome activation inhibited TLR-mediated LCN2 secretion. The inhibition of NLRP3 triggers on LCN2 secretion was caused by the inhibited transcription and translation of LCN2. At the same time, no changes in the other cytokines and IκBζ, a well-known transcriptional factor of Lcn2 transcription, were observed. Overall, NLRP3 triggers are a regulator of LCN2 expression suggesting a new linkage of inflammasome activation and LCN2 secretion in the innate immunity. Full article
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23 pages, 7409 KiB  
Article
Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells
by Chinmaya Panda, Clara Voelz, Pardes Habib, Christian Mevissen, Thomas Pufe, Cordian Beyer, Sharad Gupta and Alexander Slowik
Cells 2021, 10(7), 1652; https://doi.org/10.3390/cells10071652 - 30 Jun 2021
Cited by 24 | Viewed by 4597
Abstract
Intra-neuronal misfolding of monomeric tau protein to toxic β-sheet rich neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD). Tau pathology correlates not only with progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aβ), another pathogenic peptide involved in AD, has [...] Read more.
Intra-neuronal misfolding of monomeric tau protein to toxic β-sheet rich neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD). Tau pathology correlates not only with progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aβ), another pathogenic peptide involved in AD, has been shown to activate NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3), triggering the secretion of proinflammatory interleukin-1β (IL1β) and interleukin-18 (IL18). However, the effect of tau protein on microglia concerning inflammasome activation, microglial polarization, and autophagy is poorly understood. In this study, human microglial cells (HMC3) were stimulated with the unaggregated and aggregated forms of the tau-derived PHF6 peptide (VQIVYK). Modulation of NLRP3 inflammasome was examined by qRT-PCR, immunocytochemistry, and Western blot. We demonstrate that fibrillar aggregates of VQIVYK upregulated the NLRP3 expression at both mRNA and protein levels in a dose- and time-dependent manner, leading to increased expression of IL1β and IL18 in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on BECN1 (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy. Full article
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28 pages, 1931 KiB  
Review
NLRP3 Inflammasome at the Interface of Inflammation, Endothelial Dysfunction, and Type 2 Diabetes
by Ilona M. Gora, Anna Ciechanowska and Piotr Ladyzynski
Cells 2021, 10(2), 314; https://doi.org/10.3390/cells10020314 - 03 Feb 2021
Cited by 65 | Viewed by 7576
Abstract
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 [...] Read more.
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. Full article
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