scholarly journals Signaling Through Purinergic Receptor P2Y2 Enhances Macrophage IL-1β Production

2020 ◽  
Vol 21 (13) ◽  
pp. 4686
Author(s):  
Gonzalo de la Rosa ◽  
Ana I. Gómez ◽  
María C. Baños ◽  
Pablo Pelegrín
Keyword(s):  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Purinergic Receptor ◽  
Peritoneal Macrophages ◽  
Pharmacological Inhibition ◽  
Inflammatory Conditions ◽  
Low Concentrations ◽  
Tnf Α ◽  
Il1b Gene ◽  
Inflammatory Effect

The release of nucleotides during necrosis or apoptosis has been described to have both proinflammatory and anti-inflammatory effect on the surrounding cells. Here we describe how low concentrations of UTP and ATP applied during macrophage priming enhance IL-1β production when subsequently the NLRP3 inflammasome is activated in murine resident peritoneal macrophages. Deficiency or pharmacological inhibition of the purinergic receptor P2Y2 reverted the increase of IL-1β release induced by nucleotides. IL-1β increase was found dependent on the expression of Il1b gene and probably involving JNK activity. On the contrary, nucleotides decreased the production of a different proinflammatory cytokines such as TNF-α. These results suggest that nucleotides could shape the response of macrophages to obtain a unique proinflammatory signature that might be relevant in unrevealing specific inflammatory conditions.

scholarly journals Methylprednisolone Protects SAP and Pancreatitis-Associated ALI in Mice by Inhibiting NLRP3 Inflammasome Through NF-κB

2020 ◽  
Author(s):  
Chuan-jiang Liu ◽  
Qiang Fu ◽  
Wenjing Zhou ◽  
Xu Zhang ◽  
Rui Chen ◽  
...  
Keyword(s):  
Lung Tissue ◽  
Nlrp3 Inflammasome ◽  
Antioxidant Properties ◽  
Underlying Mechanism ◽  
Peritoneal Macrophages ◽  
Dependent Manner ◽  
Expression Levels ◽  
Tnf Α

Abstract Background: Methylprednisolone (MP) is a synthetic corticosteroid with potent anti-inflammatory and antioxidant properties used as therapy for a variety of diseases. The underlying mechanism of MP to reduce acute pancreatitis still needs to be elucidated.Methods: Twenty-four male C57BL/6 mice (6-8 weeks) were used to establish SAP mouse model by administering an intraperitoneal injection of Cae and LPS. Amylase expression levels of serum and PLF were measured with an amylase assay kit. The concentrations of IL-1β and TNF-α in the serum and PLF were detected by ELISA. The level of pancreatic and lung tissue damage and inflammation was assessed by H&E staining and immunofluorescence staining. Western blot and qPCR were used to detect the expression levels of NLRP3, IL-1β and TNF-αin vivo and in vitro.Results: In this study, we found MP, used in the early phase of SAP, decreased the levels of IL-1β and TNF-α in serum and peritoneal lavage fluids (PLF), reduced the level of serum amylase and the expression of MPO in lung tissue, attenuated the pathological injury of the pancreas and lungs in a dose-dependent manner. The expression of NLRP3 and IL-1β in pancreas and lungs was down-regulated significantly depending on the MP concentration. In vitro, MP reduced the levels of IL-1β and TNF-α by down-regulating the expression of NLRP3, IL-1β and p-NF-κB in isolated peritoneal macrophages. Conclusion: MP can attenuate the injury of pancreas and lungs, and the inflammatory response in SAP mice by down-regulating the activation of NF-κB and the NLRP3 inflammasome.

scholarly journals The Synthetic Lignan Secoisolariciresinol Diglucoside Prevents Asbestos-Induced NLRP3 Inflammasome Activation in Murine Macrophages

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Ralph A. Pietrofesa ◽  
Patrick Woodruff ◽  
Wei-Ting Hwang ◽  
Priyal Patel ◽  
Shampa Chatterjee ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Nitrosative Stress ◽  
Antioxidant Properties ◽  
Peritoneal Macrophages ◽  
Inflammasome Activation ◽  
Secoisolariciresinol Diglucoside ◽  
Nlrp3 Inflammasome Activation ◽  
Acute And Chronic Inflammation ◽  
Nlrp3 Expression

Background. The interaction of asbestos with macrophages drives two key processes that are linked to malignancy: (1) the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and (2) the activation of an inflammation cascade that drives acute and chronic inflammation, with the NLRP3 inflammasome playing a key role. Synthetic secoisolariciresinol diglucoside (SDG), LGM2605, is a nontoxic lignan with anti-inflammatory and antioxidant properties and was evaluated for protection from asbestos in murine peritoneal macrophages (MF).Methods. MFs were exposed to crocidolite asbestos ± LGM2605 given 4 hours prior to exposure and evaluated at various times for NLRP3 expression, secretion of inflammasome-activated cytokines (IL-1βand IL-18), proinflammatory cytokines (IL-6, TNFα, and HMGB1), NF-κB activation, and levels of total nitrates/nitrites.Results. Asbestos induces a significant (p<0.0001) increase in the NLRP3 subunit, release of proinflammatory cytokines, NLRP3-activated cytokines, NF-κB, and levels of nitrates/nitrites. LGM2605 significantly reduced NLRP3 ranging from 40 to 81%, IL-1βby 89–96%, and TNFαby 67–78%, as well as activated NF-κB by 48-49% while decreasing levels of nitrates/nitrites by 85–93%.Conclusions. LGM2605 reduced asbestos-induced NLRP3 expression, proinflammatory cytokine release, NF-κB activation, and nitrosative stress in MFs supporting its possible use in preventing the asbestos-induced inflammatory cascade leading to malignancy.

SIRT1 promotes macrophage polarization to enhance efferocytosis by regulating TXNIP/NLRP3 inflammasome pathway

2021 ◽  
Author(s):  
Qiao Jiang ◽  
Tongda Xu ◽  
Yang Liu ◽  
Hong Zhu ◽  
Yanfeng Ma ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Caspase 3 ◽  
Macrophage Polarization ◽  
Annexin V ◽  
Peritoneal Macrophages ◽  
Cell Polarization ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Cholesterol Intake ◽  
Cholesterol Testing

Abstract Objects: This study aimed to determine if SIRT1couldenhance efferocytosis and inhibit apoptosis by modulating cell polarization through the TXNIP/NLRP3 inflammasome pathway in murine peritoneal macrophages.Methods and Results: The effects of SIRT1in peritoneal macrophages were detected using adenovirus-mediated overexpression and knockdown of SIRT1. The apoptotic rate was determined by Annexin V/propidium iodide staining. LDLcholesterol levels were tested by Oil Red O staining and cholesterol testing. Efferocytosisof peritoneal macrophages was determined by fluorescence staining and macrophage markers were determined by flow cytometry, western blot, and ELISA.SIRT1 decreased cholesterol intake andthe apoptotic rate stimulated with ox-LDL in macrophages, which was consistent with upregulation of Bcl-2 and caspase-3 and downregulation of Bax and cleaved caspase-3. SIRT1 increased efferocytosis in macrophages. Expression levels of the M1 macrophage markers IL-6, TNF-α, iNOS, and CD16/32 were decreased, and levels of the M2 markers Dectin-1, IL-10, Arg-1, and CD206 were increased by SIRT1. Moreover, SIRT1 inhibited the ox-LDL stimulated increase in expression of TXNIP and NLRP3 proteins. The effects of SIRT1 were similar to those of TXNIP/NLRP3 inflammasome pathway inhibitor MCC950.Conclusions: These results indicated that SIRT1 exerted an anti-atherosclerosis effect by regulating macrophage polarization to enhance efferocytosis and inhibit apoptosis. Specifically, these effects were generated by downregulation of the TXNIP/NLRP3inflammasome pathway.

Perspective and Potential of A2A and A3 Adenosine Receptors as Therapeutic Targets for the Treatment of Rheumatoid Arthritis

2019 ◽  
Vol 25 (26) ◽  
pp. 2859-2874 ◽  
Author(s):  
Yogendra Pal ◽  
Nabamita Bandyopadhyay ◽  
Rashmi S. Pal ◽  
Sarfaraz Ahmed ◽  
Shantanu Bandopadhyay
Keyword(s):  
Rheumatoid Arthritis ◽  
Adenosine Receptors ◽  
Vital Role ◽  
Receptor Subtypes ◽  
Immune Disorder ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Near Future ◽  
Inflammatory Effect

Adenosine is a purine nucleoside which is an effective controller of inflammation. The inflammatory effect of adenosine is expressed via its four receptor subtypes viz. A1, A2A, A2B and A3. The various inflammatory conditions including rheumatoid arthritis (RA) are initiated by adenosine receptors of which A2A and A3 play a vital role. RA primarily is an auto-immune disorder which is manifested as chronic inflammation in the synovial lining of joints. In order to develop an effective treatment, the role of cytokines, IL–1, TNF-α and IL–6 is crucial. Besides, the knowledge of PI3K-PKB/Akt and NF-kB signaling pathway is also important to understand the antiinflammatory targets. Methotrexate along with various other molecules like, NSAIDs and DMARDs are presently used as treatment lines for controlling RA. The enhanced knowledge of the preclinical stages and pathogenesis along with recent potent therapeutics raises the hopes that RA can be prevented in the near future.

scholarly journals Tamoxifen-induced, intestinal-specific deletion of Slc5a6 in adult mice leads to spontaneous inflammation: involvement of NF-κB, NLRP3, and gut microbiota

2019 ◽  
Vol 317 (4) ◽  
pp. G518-G530 ◽  
Author(s):  
Subrata Sabui ◽  
Jonathan Skupsky ◽  
Rubina Kapadia ◽  
Kyle Cogburn ◽  
Nils W. Lambrecht ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Uptake System ◽  
Biotin Deficiency ◽  
Transport Pathway ◽  
Adult Mice ◽  
Reduced Body ◽  
Tnf Α

The sodium-dependent multivitamin transporter (SMVT; SLC5A6) is involved in intestinal absorption of vitamin B7 (biotin). We have previously shown that mice with an embryonic intestinal-specific SMVT knockout (KO) develop biotin deficiency and severe spontaneous intestinal inflammation in addition to growth retardation, developmental delays, and death within the first 6–7 wk of life. The profound morbidity and mortality associated with the SMVT-KO has limited our ability to further characterize the intestinal inflammation and other sequelae of this deletion in adult mice with a mature gut microbiota. To overcome this limitation, we generated an intestine-specific, tamoxifen-inducible, conditional SMVT-KO (SMVT-icKO). Our results showed that adult SMVT-icKO mice have reduced body weight, biotin deficiency, shorter colonic length, and bloody diarrhea compared with age- and sex-matched control littermates. All SMVT-icKO mice also developed spontaneous intestinal inflammation associated with induction of calprotectin (S100a8/S100a9), proinflammatory cytokines (IL-1β, TNF-α, IFN-γ, and IL-6), and an increase in intestinal permeability. Additionally, the intestines of SMVT-icKO showed activation of the NF-κB pathway and the nucleotide-binding domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome. Notably, administration of broad-spectrum antibiotics reduced lethality and led to normalization of intestinal inflammation, proinflammatory cytokines, altered mucosal integrity, and reduced expression of the NLRP3 inflammasome. Overall, these findings support our conclusion that the biotin transport pathway plays an important role in the maintenance of intestinal homeostasis, and that NF-κB and the NLRP3 inflammasome, as well as gut microbiota, drive the development of intestinal inflammation when SMVT is absent. NEW & NOTEWORTHY This study demonstrates that deletion of the intestinal biotin uptake system in adult mice leads to the development of spontaneous gut inflammation and that luminal microbiota plays a role in its development.

scholarly journals Vibrio alginolyticus Triggers Inflammatory Response in Mouse Peritoneal Macrophages via Activation of NLRP3 Inflammasome

2021 ◽  
Vol 11 ◽  
Author(s):  
Jinxin Wang ◽  
Qun Ding ◽  
Qiankun Yang ◽  
Hui Fan ◽  
Guili Yu ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Peritoneal Macrophages ◽  
Vibrio Alginolyticus ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Caspase 1 ◽  
Tnf Α ◽  
Mouse Peritoneal Macrophages

Vibrio alginolyticus is a food-borne marine Vibrio that causes gastroenteritis, otitis media, otitis externa, and septicemia in humans. The pathogenic mechanisms of V. alginolyticus have previously been studied in aquaculture animals; however, the underlying mechanisms in mammals remain unknown. In this study, an in vitro model of mouse peritoneal macrophages infected with V. alginolyticus was established. qPCR results revealed that V. alginolyticus induced the transcription levels of various cytokines, including IL-1β, IL-12, IL-18, TNF-α, IL-17, IL-6, IFN-γ, and IL-10, and the secretion level of IL-1β is the most significant. Inhibition assays with Ac-YVAD-CHO (a caspase-1 inhibitor) and Z-VAD-FMK (a pan-caspase inhibitor) were conducted to determine whether caspase-1 or caspase-11 is involved in V. alginolyticus-triggered IL-1β secretion. Results showed that IL-1β secretion was partly inhibited by Ac-YVAD-CHO and absolutely blocked by Z-VAD-FMK. To explore the sensed pattern recognition receptors, several NLR family members and the AIM2 receptor were detected and many receptors were upregulated especially NLRP3. Moreover, the NLRP3 protein displayed a puncta-like surrounding cell nucleus, which signified that the NLRP3 inflammasome was activated in response to V. alginolyticus infection. Inhibition assays with glyburide and CA-074 methyl ester (K+ outflow inhibitor and cathepsin B inhibitor) blocked IL-1β secretion, which demonstrated the essential role of the NLRP3 inflammasome in inflammatory response. To better understand how V. alginolyticus affects IL-1β release, the NLRP3 inflammasome was detected with doses ranging from 0.1 to 10 MOIs and time periods ranging from 3 to 12 h. Results showed that V. alginolyticus-mediated NLRP3 inflammasome activation was in a time- and dose-dependent manner and IL-1β release peaked at MOI of 1 for 12 h. Most importantly, blocking the NLRP3 inflammasome with inhibitors and the use of NLRP3-/- and caspase-1/11-/- mice could attenuate pro-inflammatory cytokine secretion, such as IL-1β, IL-6, IL-12, and TNF-α. Taken together, our study first found that the NLRP3 inflammasome plays vital roles in V. alginolyticus triggered inflammatory response in mouse peritoneal macrophages. This may provide reference information for the development of potential anti-inflammatory treatments against V. alginolyticus infection.

scholarly journals Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Activates the NLRP3 Inflammasome in Human Macrophages, Leading to the Release of Proinflammatory Cytokines

2015 ◽  
Vol 83 (4) ◽  
pp. 1487-1496 ◽  
Author(s):  
Bruce J. Shenker ◽  
David M. Ojcius ◽  
Lisa P. Walker ◽  
Ali Zekavat ◽  
Monika Damek Scuron ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Purinergic Receptor ◽  
Aggregatibacter Actinomycetemcomitans ◽  
Extracellular Atp ◽  
Ros Generation ◽  
Inflammasome Activation ◽  
Cytolethal Distending Toxin ◽  
Content Type ◽  
Atp Levels

The cytolethal distending toxin (Cdt) is produced from a number of bacteria capable of causing infection and inflammatory disease. Our previous studies withActinobacillus actinomycetemcomitansCdt demonstrate not only that the active toxin subunit functions as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase but also that macrophages exposed to the toxin were stimulated to produce proinflammatory cytokines. We now demonstrate that the Cdt-induced proinflammatory response involves the activation of the NLRP3 inflammasome. Specific inhibitors and short hairpin RNA (shRNA) were employed to demonstrate requirements for NLRP3 and ASC as well as caspase-1. Furthermore, Cdt-mediated inflammasome activation is dependent upon upstream signals, including reactive oxygen species (ROS) generation and Cdt-induced increases in extracellular ATP levels. Increases in extracellular ATP levels contribute to the activation of the P2X7purinergic receptor, leading to K+efflux. The relationship between the abilities of the active toxin subunit CdtB to function as a lipid phosphatase, activate the NLRP3 inflammasome, and induce a proinflammatory cytokine response is discussed. These studies provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms such asAggregatibacter actinomycetemcomitans.

scholarly journals The Anti-Inflammatory Effect of Smilax china L. Extract on LPS-Stimulated THP-1 via Downregulation of MAPK and NF-κB Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Siyi Jiang ◽  
Qiong Wei ◽  
Xiaochuan Ye ◽  
Dan Luo ◽  
Xiaoyan Zhang ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Positive Control ◽  
Inflammatory Activity ◽  
Mrna Levels ◽  
Tnf Α ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1 ◽  
Inflammatory Effect

Background. Traditional Chinese medicine Smilax is the rhizome of liliaceous plant Smilax china L., which is used to treat pelvic inflammatory disease and anxieties. Purpose. To investigate the mechanism of anti-inflammatory activity of the extract from Smilax china L. (ES). Methods. The components of ES were identified by UPLC-QTOF-MS/MS. The anti-inflammatory activities were evaluated in xylene-induced ear oedema and egg white-induced plantar swelling test. Cell viability was examined by CCK-8 assay. The inflammatory mediators, proinflammatory cytokines, and MAPK and NF-κB signals in LPS-stimulated THP-1 cells were determined using ELISA, real-time PCR, and Western blot, respectively. Results. 20 compounds of ES were confirmed by comparing with the reference substance. ES displayed more prominent anti-inflammatory activity than the positive control “Jin Gang Teng” capsule in the in vivo acute inflammatory model. ES suppressed the expression of PGE2 and 6-Keot-PGF1α, and the ratio of IC50 (COX-1)/IC50 (COX-2) of ES was 3.15, which indicated that ES could selectively inhibit COX-2. ES dose-dependently (12.5, 25, and 50 mg/L) decreased the production and mRNA levels of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Furthermore, ES significantly decreased LPS-induced phosphorylation of p38, JNK, ERK1/2, and p65, inhibiting the expression of IKKα and the degradation of IκBα. Conclusion. The results suggested that ES could selectively inhibit the activity of COX-2, and the anti-inflammatory effect of ES was associated with the inhibition of IL-1β, IL-6, and TNF-α via negative regulation of MAPK and NF-κB signaling pathways in LPS-induced THP-1 cells.

scholarly journals Do proinflammatory cytokines play a role in clozapine-associated glycometabolism disorders?

2021 ◽  
Author(s):  
Tongtong Zhao ◽  
Kai Zhang ◽  
Yelei Zhang ◽  
Yating Yang ◽  
Xiaoshuai Ning ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Side Effects ◽  
Proinflammatory Cytokines ◽  
Peripheral Blood ◽  
Animal Experiments ◽  
Pancreatic Tissue ◽  
Mouse Serum ◽  
Healthy Controls ◽  
Immunological Mechanisms ◽  
Tnf Α

Abstract Rationale and objective Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders. Methods We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue. Results Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients’ BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α. Conclusion Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.

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