scholarly journals PCB118 Induces Inflammation of Islet Beta Cells via Activating ROS-NLRP3 Inflammasome Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Chunxia Jiang ◽  
Yuping Wang ◽  
Man Guo ◽  
Yang Long ◽  
Jiao Chen ◽  
...  
Keyword(s):  
Beta Cells ◽  
Endocrine Disruptors ◽  
Nlrp3 Inflammasome ◽  
Clinical Syndrome ◽  
Cell Counting ◽  
Dependent Manner ◽  
Mouse Islet ◽  
Islet Beta Cells ◽  
Caspase 1 ◽  
Environmental Endocrine Disruptors

Background. Diabetes mellitus is a clinical syndrome caused by genetic and environmental factors. Growing evidence suggests that exposure to environmental endocrine disruptors and activation of NLRP3 inflammasome signaling play a vital role in diabetes. However, it is unclear how PCB118, a common environmental endocrine disruptor, contributes to the incidence of diabetes, and its specific mechanism of action is unknown. In this study, we explored whether ROS-induced NLRP3 inflammasome priming and activation were related to PCB118 exposure in mouse islet β-TC-6 cells and the mechanisms of diabetes. Methods. Mouse islet β-TC-6 cells were cultured with PCB118 as a stimulating factor and ROS inhibitor N-acetyl cysteine (NAC) as an intervention. Cellular toxicity due to PCB118 was detected using the Cell Counting Kit-8; ROS was measured using DCFH-DA; the expressions of NLRP3, procaspase-1, caspase-1, pro-IL-1β, and IL-1β protein were detected by western blot; and IL-6, IL-18, and C-C chemokine ligand 2 (CCL-2) were measured by ELISA. Results. PCB118 caused significant toxicity to the cells when the stimulation concentration was equal to or greater than 80 nmol/L at 72 hours ( p < 0.05 ) and increased the levels of ROS, NLRP3, caspase-1, IL-1β, IL-6, IL-18, and CCL-2 ( p < 0.05 ); the expressions of procaspase-1 and pro-IL-1β were downregulated in a dose-dependent manner after PCB118 exposure ( p < 0.05 ), which was prevented by pretreatment with NAC ( p < 0.05 ). Conclusions. PCB118 can activate NLRP3 inflammasome signaling in islet beta cells via the oxidative stress pathway and cause inflammation in islet beta cells. It suggests that environmental endocrine disruptors play an important role in the inflammation of islet beta cells and may contribute to the development of diabetes through NLRP3 inflammatory signaling.

scholarly journals Shiga Toxins Activate the NLRP3 Inflammasome Pathway To Promote Both Production of the Proinflammatory Cytokine Interleukin-1β and Apoptotic Cell Death

2015 ◽  
Vol 84 (1) ◽  
pp. 172-186 ◽  
Author(s):  
Moo-Seung Lee ◽  
Haenaem Kwon ◽  
Eun-Young Lee ◽  
Dong-Jae Kim ◽  
Jong-Hwan Park ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Interleukin 1Β ◽  
Dependent Manner ◽  
Shiga Toxins ◽  
Caspase 1 ◽  
Immune Signaling Pathway ◽  
Tnf Α

Shiga toxin (Stx)-mediated immune responses, including the production of the proinflammatory cytokines tumor necrosis-α (TNF-α) and interleukin-1β (IL-1β), may exacerbate vascular damage and accelerate lethality. However, the immune signaling pathway activated in response to Stx is not well understood. Here, we demonstrate that enzymatically active Stx, which leads to ribotoxic stress, triggers NLRP3 inflammasome-dependent caspase-1 activation and IL-1β secretion in differentiated macrophage-like THP-1 (D-THP-1) cells. The treatment of cells with a chemical inhibitor of glycosphingolipid biosynthesis, which suppresses the expression of the Stx receptor globotriaosylceramide and subsequent endocytosis of the toxin, substantially blocked activation of the NLRP3 inflammasome and processing of caspase-1 and IL-1β. Processing and release of both caspase-1 and IL-1β were significantly reduced or abolished in Stx-intoxicated D-THP-1 cells in which the expression of NLRP3 or ASC was stably knocked down. Furthermore, Stx mediated the activation of caspases involved in apoptosis in an NLRP3- or ASC-dependent manner. In Stx-intoxicated cells, the NLRP3 inflammasome triggered the activation of caspase-8/3, leading to the initiation of apoptosis, in addition to caspase-1-dependent pyroptotic cell death. Taken together, these results suggest that Stxs trigger the NLRP3 inflammasome pathway to release proinflammatory IL-1β as well as to promote apoptotic cell death.

scholarly journals Z-ligustilide protects BV-2 microglial cells against oxygen-glucose deprivation/reoxygenation-induced injury by inhibiting NLRP3 inflammasome activation and pyroptosis

2020 ◽  
Vol 18 ◽  
pp. 205873922093492
Author(s):  
Jia Hu ◽  
Jie Wei ◽  
Cheng Zeng ◽  
Fengqi Duan ◽  
Sijun Liu ◽  
...  
Keyword(s):  
Cell Viability ◽  
Nlrp3 Inflammasome ◽  
Glucose Deprivation ◽  
Microglial Cells ◽  
Cell Counting ◽  
Oxygen Glucose Deprivation ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Active Caspase

Z-ligustilide (LIG) is the main bioactive compound of Danggui essential oil, which was reported to exert neuroprotective and anti-inflammatory effects. However, the underlying mechanism remains largely elusive. The present study aims to investigate the effect of LIG on oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury and whether Nod-like receptor protein 3 (NLRP3) inflammasome and related pyroptosis are targets for the treatment of LIG. The OGD/R model was established in BV-2 microglial cells to investigate the protective effect of LIG. Cell viability and the release of lactate dehydrogenase (LDH) were determined by cell counting assay kit 8 and the LDH release assay kit. Western blot and immunofluorescence staining were carried out to detect NLRP3 inflammasome activation and pyroptosis. Active caspase-1 and TdT-mediated dUTP nick end labeling (TUNEL) double positive cells were defined as pyroptosis population. Statistical comparison among multiple groups was carried out by one-way analysis of variance (ANOVA) followed by least significant difference (LSD) test. Compared with control cells, OGD/R impaired cell viability and induced the release of LDH in BV-2 microglial cells, which were associated with the activation of NLRP3 inflammasome as evidenced by increased expression of NLRP3 and the cleavage of caspase-1 and interleukin-1 beta (IL-1β). In parallel with NLRP3 inflammasome activation, OGD/R induced pyroptotic cell death, manifested by the cleavage of gasdermin D (GSDMD) and increased population of active caspase-1+/TUNEL+ cells. All these events were significantly attenuated by treatment with LIG, indicating that LIG significantly inhibited NLRP3 inflammasome activation and pyroptosis, and ameliorated OGD/R-induced cell injury. In conclusion, LIG protects BV-2 microglial cells against OGD/R-induced injury via inhibition of NLRP3 inflammasome and pyroptosis.

scholarly journals Overexpression of beta 2-microglobulin in transgenic mouse islet beta cells results in defective insulin secretion.

1991 ◽  
Vol 88 (6) ◽  
pp. 2070-2074 ◽  
Author(s):  
J. Allison ◽  
L. Malcolm ◽  
J. Culvenor ◽  
R. K. Bartholomeusz ◽  
K. Holmberg ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Transgenic Mouse ◽  
Beta Cells ◽  
Mouse Islet ◽  
Islet Beta Cells ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Glucose-induced electrical activity in pancreatic beta-cell: modulation by pH

1981 ◽  
Vol 241 (5) ◽  
pp. C264-C268 ◽  
Author(s):  
J. T. Tarvin ◽  
G. Sachs ◽  
C. S. Pace
Keyword(s):  
Beta Cell ◽  
Electrical Activity ◽  
Beta Cells ◽  
Pancreatic Beta Cell ◽  
Weak Acid ◽  
Weak Base ◽  
Extracellular Acidification ◽  
Mouse Islet ◽  
Islet Beta Cells ◽  
Oscillatory Pattern

Studies have been undertaken to examine the influence of changes in pH on the electrical activity in mouse islet beta-cells. Extracellular acidification or the presence of the permeable weak acid glycodiazine was found to alter the cyclic nature of glucose-induced electrical activity leading to depolarization and constant spike activity. Conversely, the presence of the permeable weak base imidazole was found to transiently lead to hyperpolarization with concomitant inhibition of electrical activity. Monensin, an electroneutral Na:H antiporter, was found to inhibit glucose-induced electrical activity, even in the presence of glycodiazine. These results suggest that protons may play an important role in the regulation and/or generation of the oscillatory pattern of electrical activity in the beta-cell.

scholarly journals Danger-associated molecular pattern molecules take unexpectedly a central stage in Nlrp3 inflammasome–caspase-1-mediated trafficking of hematopoietic stem/progenitor cells

Leukemia ◽  
2021 ◽  
Author(s):  
Arjun Thapa ◽  
Mateusz Adamiak ◽  
Kamila Bujko ◽  
Janina Ratajczak ◽  
Ahmed K. Abdel-Latif ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Nlrp3 Inflammasome ◽  
Sterile Inflammation ◽  
Dependent Manner ◽  
Proteolytic Activation ◽  
Hematopoietic Stem ◽  
Caspase 1 ◽  
Molecular Pattern ◽  
First Time ◽  
Deficient Mice

AbstractLike their homing after transplantation to bone marrow (BM), the mobilization of hematopoietic stem/progenitor cells (HSPCs) is still not fully understood, and several overlapping pathways are involved. Several years ago our group proposed that sterile inflammation in the BM microenvironment induced by pro-mobilizing agents is a driving force in this process. In favor of our proposal, both complement cascade (ComC)-deficient and Nlrp3 inflammasome-deficient mice are poor G-CSF and AMD3100 mobilizers. It is also known that the Nlrp3 inflammasome mediates its effects by activating caspase-1, which is responsible for proteolytic activation of interleukin-1β (IL-1β) and interleukin-18 (IL-18) and their release from cells along with several danger-associated molecular pattern molecules (DAMPs). We observed in the past that IL-1β and IL-18 independently promote mobilization of HSPCs. In the current work we demonstrated that caspase-1-KO mice are poor mobilizers, and, to our surprise, administration of IL-1β or IL-18, as in the case of Nlrp3-KO animals, does not correct this defect. Moreover, neither Caspase-1-KO nor Nlrp3-KO mice properly activated the ComC to execute the mobilization process. Interestingly, mobilization in these animals and activation of the ComC were both restored after injection of the DAMP cocktail eATP+HGMB1+S100A9, the components of which are normally released from cells in an Nlrp3 inflammasome–caspase-1-dependent manner. In addition, we report that caspase-1-deficient HSPCs show a decrease in migration in response to BM homing factors and engraft more poorly after transplantation. These results for the first time identify caspase-1 as an orchestrator of HSPC trafficking.

scholarly journals Cold-Inducible RNA-Binding Protein (CIRP) Potentiates Uric Acid-Induced IL-1β Production

2021 ◽  
Author(s):  
Yuya Fujita ◽  
Toru Yago ◽  
Haruki Matsumoto ◽  
Tomoyuki Asano ◽  
Naoki Matsuoka ◽  
...  
Keyword(s):  
Uric Acid ◽  
Nlrp3 Inflammasome ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Human Neutrophils ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Caspase 1

Abstract Background Gout is an autoinflammatory disease driven by interleukin-1 (IL-1) induction in response to uric acid crystals. IL-1β production is dependent on inflammasome activation, which requires a priming signal, followed by an activating signal. The cold-inducible RNA-binding protein (CIRP) has been recently identified as a damage-associated molecular pattern (DAMP). In this study, we evaluated the roles of CIRP in monosodium urate (MSU)-mediated IL-1β secretion using human neutrophils. Methods Human neutrophils were stimulated by MSU in the presence or absence of CIRP priming to determine NLRP3 inflammasome activation and subsequent caspase-1 activation and IL-1β production. Cellular supernatants were analyzed by enzyme-linked immunosorbent assay (ELISA) to determine the presence of IL-1β or caspase-1 (p20). The cellular supernatants and lysates were also analyzed by immunoblotting using anti-cleaved IL-1β or anti-cleaved caspase-1 antibodies. Additionally, pro-IL-1β and NLRP3 transcript levels were analyzed by real-time reverse transcription-PCR (RT-PCR). Results Neither CIRP nor MSU stimulation alone induced sufficient IL-1β secretion from neutrophils. However, MSU stimulation induced IL-1β secretion from CIRP-primed neutrophils in a dose-dependent manner. This MSU-induced IL-1β secretion from CIRP-primed neutrophils was accompanied by the induction of cleaved IL-1β (p17). Furthermore, cleaved caspase-1 was induced in the cellular lysates of CIRP/MSU-treated neutrophils. Additionally, CIRP stimulation induced the expression of pro-IL-1β mRNA and protein in neutrophils. Conclusions Our data indicate that CIRP, an endogenous stress molecule, triggers uric acid-induced mature IL-1β induction as a priming stimulus for NLRP3 inflammasome in human neutrophils. We propose that CIRP acts as an important proinflammatory stimulant that primes and activates inflammasome and pro-IL-1β processing in response to uric acid in innate immune cells.

scholarly journals Juglone Suppresses LPS-induced Inflammatory Responses and NLRP3 Activation in Macrophages

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3104 ◽  
Author(s):  
Nam-Hun Kim ◽  
Hong-Ki Kim ◽  
Ji-Hak Lee ◽  
Seung-Il Jo ◽  
Hye-Min Won ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
No Production ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Inflammatory Cytokine Production ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome has been implicated in a variety of diseases, including atherosclerosis, neurodegenerative diseases, and infectious diseases. Thus, inhibitors of NLRP3 inflammasome have emerged as promising approaches to treat inflammation-related diseases. The aim of this study was to explore the effects of juglone (5-hydroxyl-1,4-naphthoquinone) on NLRP3 inflammasome activation. The inhibitory effects of juglone on nitric oxide (NO) production were assessed in lipopolysaccharide (LPS)-stimulated J774.1 cells by Griess assay, while its effects on reactive oxygen species (ROS) and NLRP3 ATPase activity were assessed. The expression levels of NLRP3, caspase-1, and pro-inflammatory cytokines (IL-1β, IL-18) and cytotoxicity of juglone in J774.1 cells were also determined. Juglone was non-toxic in J774.1 cells when used at 10 μM (p < 0.01). Juglone treatment inhibited the production of ROS and NO. The levels of NLRP3 and cleaved caspase-1, as well as the secretion of IL-1β and IL-18, were decreased by treatment with juglone in a concentration-dependent manner. Juglone also inhibited the ATPase activities of NLRP3 in LPS/ATP-stimulated J774.1 macrophages. Our results suggested that juglone could inhibit inflammatory cytokine production and NLRP3 inflammasome activation in macrophages, and should be considered as a therapeutic strategy for inflammation-related diseases.

scholarly journals Activation of NLRP3 by uropathogenic Escherichia coli is associated with IL-1β release and regulation of antimicrobial properties in human neutrophils

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Isak Demirel ◽  
Alexander Persson ◽  
Annelie Brauner ◽  
Eva Särndahl ◽  
Robert Kruse ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Nlrp3 Inflammasome ◽  
Serine Proteases ◽  
Antimicrobial Properties ◽  
Human Neutrophils ◽  
Dependent Manner ◽  
Upec Strain ◽  
Caspase 1 ◽  
Strain Cft073

AbstractThe NLRP3 inflammasome and IL-1β have recently been linked to the severity of uropathogenic Escherichia coli (UPEC)-mediated urinary tract infection (UTI). However, not much is known about the contribution of NLRP3 to the antimicrobial properties of neutrophils and the release of IL-1β during UPEC infection. The purpose of this study was to elucidate the mechanisms behind UPEC-induced IL-1β release from human neutrophils, and to investigate the contribution of the NLRP3 inflammasome in neutrophil-mediated inhibition of UPEC growth. We found that the UPEC strain CFT073 increased the expression of NLRP3 and increased caspase-1 activation and IL-1β release from human neutrophils. The IL-1β release was mediated by the NLRP3 inflammasome and by serine proteases in an NF-κB-and cathepsin B-dependent manner. The UPEC virulence factors α-hemolysin, type-1 fimbriae and p-fimbriae were all shown to contribute to UPEC mediated IL-1β release from neutrophils. Furthermore, inhibition of caspase-1 and NLRP3 activation increased neutrophil ROS-production, phagocytosis and the ability of neutrophils to suppress UPEC growth. In conclusion, this study demonstrates that UPEC can induce NLRP3 and serine protease-dependent release of IL-1β from human neutrophils and that NLRP3 and caspase-1 can regulate the antimicrobial activity of human neutrophils against UPEC.

scholarly journals Endoplasmic reticulum calcium store regulates membrane potential in mouse islet beta-cells.

1994 ◽  
Vol 269 (20) ◽  
pp. 14359-14362
Author(s):  
J.F. Worley ◽  
M.S. McIntyre ◽  
B. Spencer ◽  
R.J. Mertz ◽  
M.W. Roe ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Potential ◽  
Beta Cells ◽  
Calcium Store ◽  
Mouse Islet ◽  
Islet Beta Cells ◽  
Endoplasmic Reticulum Calcium
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