scholarly journals Molecularly Distinct NLRP3 Inducers Mediate Diverse Ratios of Interleukin-1β and Interleukin-18 from Human Monocytes

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Kristine Midtbö ◽  
Daniel Eklund ◽  
Eva Särndahl ◽  
Alexander Persson
Keyword(s):  
Nlrp3 Inflammasome ◽  
Adaptive Immune Response ◽  
Inflammasome Activation ◽  
Interleukin 18 ◽  
Adaptive Immune ◽  
Important Mediator ◽  
Nlrp3 Inflammasome Activation ◽  
The Difference ◽  
Inflammasome Activity ◽  
Different Doses

Inflammasomes cleave and activate interleukin- (IL-) 1β and IL-18 which have both shared and unique biological functions. IL-1β is an important mediator of the acute phase response to infections and tissue damage, whereas IL-18 takes part in activation and tailoring of the adaptive immune response. While IL-1β has served as the prototypic indicator of inflammasome activation, few studies have compared the potential differences in IL-1β and IL-18 production during inflammasome activation. Since these cytokines partake in different immune pathways, the involvement of inflammasome activity in different conditions needs to be described beyond IL-1β production alone. To address a potential heterogeneity in inflammasome functionality, ATP, chitosan, or silica oxide (SiO2) were used to induce NLRP3 inflammasome activation in THP-1 cells and the subsequent outcomes were quantified. Despite using doses of the inflammasome inducers yielding similar release of IL-1β, SiO2-stimulated cells showed a lower concentration of released IL-18 compared to ATP and chitosan. Hence, the cells stimulated with SiO2 responded with a distinctly different IL-18 : IL-1β ratio. The difference in the IL-18 : IL-1β ratio for SiO2 was constant over different doses. While all downstream responses were strictly dependent on a functional NLRP3 inflammasome, the differences did not depend on the level of gene expression, caspase-1 activity, or pyroptosis. We suggest that the NLRP3 inflammasome response should be considered a dynamic process, which can be described by taking the ratio between IL-1β and IL-18 into account and moving away from an on/off perspective of inflammasome activation.

Adaptive immune response during acute pancreatitis is regulated by NLRP3 inflammasome activation via interleukin 18

Pancreatology ◽  
2018 ◽  
Vol 18 (4) ◽  
pp. S87-S88
Author(s):  
Matthias Sendler ◽  
Cindy van den Brandt ◽  
Juliane Glaubitz ◽  
Anika Wilden ◽  
F. Ulrich Weiss ◽  
...  
Keyword(s):  
Immune Response ◽  
Acute Pancreatitis ◽  
Nlrp3 Inflammasome ◽  
Adaptive Immune Response ◽  
Inflammasome Activation ◽  
Interleukin 18 ◽  
Adaptive Immune ◽  
Nlrp3 Inflammasome Activation

scholarly journals IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy

2021 ◽  
Vol 12 ◽  
Author(s):  
Mehboob Ali ◽  
Mehak Gupta ◽  
Abubakar Wani ◽  
Ankita Sharma ◽  
Mohd Abdullaha ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inhibitory Activity ◽  
Inflammatory Diseases ◽  
Inflammasome Activation ◽  
Synthetic Compound ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α ◽  
Pathological Development ◽  
Inflammasome Activity ◽  
Nlrp3 Activity

Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate NLRP3 inflammasome activity. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP induced NLRP3 inflammasome by induction of autophagy through AMPK pathway in bone marrow derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was significantly reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated inhibitory activity of IIIM-941 against NLRP3 in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in ATP induced peritoneal inflammation model. IIIM-941 was similarly effective in suppressing MSU induced IL-1β in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in MSU indued foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer’s disease and Parkinson’s disease, where hampered autophagy and NLRP3 activation play a crucial role in the pathological development.

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 ◽  
Saresella Marina ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Beclin 1 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Beneficial Effects ◽  
Nlrp3 Inflammasome Activation ◽  
Chaperone Mediated Autophagy ◽  
Inflammasome Activity

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. Methods 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 inflammasome activity by measuring NLRP3-ASC complexes formation by AMNIS Flow-sight and pro-inflammatory cytokines (IL-1β, IL-18 and Caspase-1) production by enzyme-linked immunosorbent assay (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 proinflammatory 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 Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2297
Author(s):  
Sonia Missiroli ◽  
Mariasole Perrone ◽  
Caterina Boncompagni ◽  
Chiara Borghi ◽  
Alberto Campagnaro ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Therapeutic Option ◽  
Anticancer Therapy ◽  
New Drugs ◽  
Inflammasome Activation ◽  
Interleukin 18 ◽  
Nlrp3 Inflammasome Activation ◽  
Therapy Target

Inflammasomes are multiprotein complexes that regulate the maturation and secretion of the proinflammatory cytokines interleukin-1beta (IL-1βand interleukin-18 (IL-18) in response to various intracellular stimuli. As a member of the inflammasomes family, NLRP3 is the most studied and best characterized inflammasome and has been shown to be involved in several pathologies. Recent findings have made it increasingly apparent that the NLRP3 inflammasome may also play a central role in tumorigenesis, and it has attracted attention as a potential anticancer therapy target. In this review, we discuss the role of NLRP3 in the development and progression of cancer, offering a detailed summary of NLRP3 inflammasome activation (and inhibition) in the pathogenesis of various forms of cancer. Moreover, we focus on the therapeutic potential of targeting NLRP3 for cancer therapy, emphasizing how understanding NLRP3 inflammasome-dependent cancer mechanisms might guide the development of new drugs that target the inflammatory response of tumor-associated cells.

scholarly journals Recruitment of pro-IL-1α to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation

2020 ◽  
Vol 118 (1) ◽  
pp. e2015632118
Author(s):  
Jargalsaikhan Dagvadorj ◽  
Karolina Mikulska-Ruminska ◽  
Gantsetseg Tumurkhuu ◽  
Rojo A. Ratsimandresy ◽  
Jessica Carriere ◽  
...  
Keyword(s):  
Computational Modeling ◽  
Nlrp3 Inflammasome ◽  
Mitochondrial Damage ◽  
Binding Motif ◽  
Inflammasome Activation ◽  
Activated Macrophages ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Interleukin 1Α ◽  
Inflammasome Activity

The balance between NLRP3 inflammasome activation and mitophagy is essential for homeostasis and cellular health, but this relationship remains poorly understood. Here we found that interleukin-1α (IL-1α)–deficient macrophages have reduced caspase-1 activity and diminished IL-1β release, concurrent with reduced mitochondrial damage, suggesting a role for IL-1α in regulating this balance. LPS priming of macrophages induced pro-IL-1α translocation to mitochondria, where it directly interacted with mitochondrial cardiolipin (CL). Computational modeling revealed a likely CL binding motif in pro-IL-1α, similar to that found in LC3b. Thus, binding of pro-IL-1α to CL in activated macrophages may interrupt CL-LC3b–dependent mitophagy, leading to enhanced Nlrp3 inflammasome activation and more robust IL-1β production. Mutation of pro-IL-1α residues predicted to be involved in CL binding resulted in reduced pro-IL-1α–CL interaction, a reduction in NLRP3 inflammasome activity, and increased mitophagy. These data identify a function for pro-IL-1α in regulating mitophagy and the potency of NLRP3 inflammasome activation.

scholarly journals Autophagy Inhibition Contributes to ROS-Producing NLRP3-Dependent Inflammasome Activation and Cytokine Secretion in High Glucose-Induced Macrophages

2017 ◽  
Vol 43 (1) ◽  
pp. 247-256 ◽  
Author(s):  
Jiezhi Dai ◽  
Xiaotian Zhang ◽  
Li Li ◽  
Hua  Chen ◽  
Yimin Chai
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Cytokine Secretion ◽  
Inflammasome Activation ◽  
Ros Production ◽  
Oxygen Species ◽  
Nlrp3 Inflammasome Activation ◽  
Diabetic Wounds ◽  
Autophagy Inhibition ◽  
Inflammasome Activity

Background: Type 2 diabetes is a persistent inflammatory response that impairs the healing process. We hypothesized that stimulation with high glucose following a pro-inflammatory signal would lead to autophagy inhibition, reactive oxygen species (ROS) production and eventually to the activation of the Nod-like receptor protein (NLRP) -3. Methods: Macrophages were isolated from human diabetic wound. We measured the expression of NLRP3, caspase1 and interleukin-1 beta (IL-1β) by western blot and real-time PCR, and the surface markers on cells by flow cytometry. THP-1-derived macrophages exposed to high glucose were applied to study the link between autophagy, ROS and NLRP3 activation. LC3-II, P62, NLRP3 inflammation and IL-1β expression were measured by western blot and real-time PCR. ROS production was measured with a Cellular Reactive Oxygen Species Detection Assay Kit. Results: Macrophages isolated from diabetic wounds exhibited a pro-inflammatory phenotype, including sustained NLRP3 inflammasome activity associated with IL-1β secretion. Our data showed that high glucose inhibited autophagy, induced ROS production, and activated NLRP3 inflammasome and cytokine secretion in THP-1-derived macrophages. To study high glucose-induced NLRP3 inflammasome signalling, we performed studies using an autophagy inducer, a ROS inhibitor and a NLRP3 inhibitor and found that all reduced the NLRP3 inflammasome activation and cytokine secretion. Conclusion: Sustained NLRP3 inflammasome activity in wound-derived macrophages contributes to the hyper-inflammation in human diabetic wounds. Autophagy inhibition and ROS generation play an essential role in high glucose-induced NLRP3 inflammasome activation and cytokine secretion in macrophages.

scholarly journals Inhibition of the Inflammasome Activity of NLRP3 Attenuates HDM-Induced Allergic Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Ming Ma ◽  
Guoyang Li ◽  
Minghui Qi ◽  
Wei Jiang ◽  
Rongbin Zhou
Keyword(s):  
Inflammatory Response ◽  
Allergic Asthma ◽  
Nlrp3 Inflammasome ◽  
Treatment Options ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Nlrp3 Inflammasome Activation ◽  
Dust Mite ◽  
New Treatment ◽  
Inflammasome Activity

Inhaled allergens promote inflammatory response, tissue damage, and airway hyperresponsiveness in the lungs, leading to allergic asthma. NLRP3, as an immune sensor of infections and cellular stress, is associated with the development and exacerbation of asthma. However, the mechanism by which NLRP3 affects asthma requires further investigation. Here, we showed that inhaled house dust mite (HDM) promotes NLRP3 inflammasome activation in the lungs and specifically induces the maturation of caspase-1 and IL-1β in alveolar macrophages (AMs). Using Nlrp3-mutant mice, we found that NLRP3 promotes the inflammatory response and pathogenesis in HDM-induced allergic asthma in an inflammasome-dependent manner. Treatment with RRx-001, an NLRP3 inhibitor, significantly reduced inflammatory cell infiltration and mucus secretion in the airway. Our results showed that NLRP3 in myeloid cells promoted the development and progression of allergic asthma in an inflammasome-dependent manner. Small molecules targeting the NLRP3 inflammasome may provide new treatment options for this disease.

scholarly journals Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 47
Author(s):  
Mark F. McCarty ◽  
Simon Bernard Iloki Assanga ◽  
Lidianys Lewis Luján ◽  
James H. O’Keefe ◽  
James J. DiNicolantonio
Keyword(s):  
Nlrp3 Inflammasome ◽  
Protein Complexes ◽  
Interleukin 1Β ◽  
Inflammasome Activation ◽  
Interleukin 18 ◽  
Medical Disorders ◽  
Nlrp3 Inflammasome Activation ◽  
Wide Range ◽  
Stress Signals ◽  
And Control

Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1β and pro-interleukin-18 to active interleukin-1β and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation—including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity—antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.

scholarly journals Role of Lysosomes in Silica-Induced Inflammasome Activation and Inflammation in Absence of MARCO

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Rupa Biswas ◽  
Raymond F. Hamilton ◽  
Andrij Holian
Keyword(s):  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Scavenger Receptor ◽  
Acid Sphingomyelinase ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
The Difference ◽  
Silica Treatment

MARCO is the predominant scavenger receptor for recognition and binding of silica particles by alveolar macrophages (AM). Previously, it was shown that mice null for MARCO have a greater inflammatory response to silica, but the mechanism was not described. The aim of this study was to determine the relationship between MARCO and NLRP3 inflammasome activity. Silica increased NLRP3 inflammasome activation and release of the proinflammatory cytokine, IL-1β, to a greater extent in MARCO−/−AM compared to wild type (WT) AM. Furthermore, in MARCO−/−AM there was greater cathepsin B release from phagolysosomes, Caspase-1 activation, and acid sphingomyelinase activity compared to WT AM, supporting the critical role played by lysosomal membrane permeabilization (LMP) in triggering silica-induced inflammation. The difference in sensitivity to LMP appears to be in cholesterol recycling since increasing cholesterol in AM by treatment with U18666A decreased silica-induced NLRP3 inflammasome activation, and cells lacking MARCO were less able to sequester cholesterol following silica treatment. Taken together, these results demonstrate that MARCO contributes to normal cholesterol uptake in macrophages; therefore, in the absence of MARCO, macrophages are more susceptible to a greater inflammatory response by particulates known to cause NLRP3 inflammasome activation and the effect is due to increased LMP.

scholarly journals C646 Protects Against DSS-Induced Colitis Model by Targeting NLRP3 Inflammasome

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueming Xu ◽  
Jing Li ◽  
Xiuyan Long ◽  
Sifan Tao ◽  
Xiaoyu Yu ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Nlrp3 Inflammasome ◽  
Histone Acetyltransferase ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Tnf Α ◽  
Inflammatory Bowel ◽  
Inflammasome Activity ◽  
Colitis Model ◽  
Pro Inflammatory Cytokines

Numerous pieces of evidence have identified that the NLRP3 inflammasome plays a pivotal role in the development and pathogenesis of colitis. Targeting the NLRP3 inflammasome represents a potential therapeutic treatment. Our previous studies have suggested that acetylation of NLRP3 is indispensable to NLRP3 inflammasome activation, and some acetyltransferase inhibitors could suppress the NLRP3 inflammasome activation. Here, we identified that C646, an inhibitor of histone acetyltransferase p300, exerts anti-inflammatory effects in DSS-induced colitis mice by targeting the NLRP3 inflammasome. Mechanistically, C646 not only inhibits NF-κB activation, leading to the decreased expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and NLRP3, but also suppresses the NLRP3 inflammasome assembly by disrupting the interaction between NLRP3 and ASC. In addition, C646 attenuated the LPS-induced acute systemic inflammation model. Thus, our results demonstrate the ability of C646 to suppress the NLRP3 inflammasome activity and its potential application in the treatment of inflammatory bowel disease.

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