scholarly journals Sphingosine Kinases are Involved in Macrophage NLRP3 Inflammasome Transcriptional Induction

2020 ◽  
Vol 21 (13) ◽  
pp. 4733
Author(s):  
Shahzad Nawaz Syed ◽  
Andreas Weigert ◽  
Bernhard Brüne
Keyword(s):  
Nlrp3 Inflammasome ◽  
De Novo ◽  
Inflammasome Activation ◽  
Relative Contribution ◽  
Mouse Macrophages ◽  
Sphingosine Kinases ◽  
Transcriptional Induction ◽  
Human And Mouse ◽  
Inflammasome Activity

Recent studies suggested an important contribution of sphingosine-1-phospate (S1P) signaling via its specific receptors (S1PRs) in the production of pro-inflammatory mediators such as Interleukin (IL)-1β in cancer and inflammation. In an inflammation-driven cancer setting, we previously reported that myeloid S1PR1 signaling induces IL-1β production by enhancing NLRP3 (NOD-, LRR- and Pyrin Domain-Containing Protein 3) inflammasome activity. However, the autocrine role of S1P and enzymes acting on the S1P rheostat in myeloid cells are unknown. Using human and mouse macrophages with pharmacological or genetic intervention we explored the relative contribution of sphingosine kinases (SPHKs) in NLRP3 inflammasome activity regulation. We noticed redundancy in SPHK1 and SPHK2 activities towards macrophage NLRP3 inflammasome transcriptional induction and IL-1β secretion. However, pharmacological blockade of both kinases in unison completely abrogated NLRP3 inflammasome induction and IL-1β secretion. Interestingly, human and mouse macrophages demonstrate varied responses towards SPHKs inhibition and IL-1β secretion. Clinical datasets of renal cell carcinoma and psoriasis patients showed a positive correlation between enzymes affecting the S1P rheostat with NLRP3 inflammasome components expression, which corroborates our finding. Our data provide a better understanding on the role of SPHKs and de novo synthesized S1P in macrophage NLRP3 inflammasome activation.

scholarly journals Epigallocatechin-3-Gallate Prevents Acute Gout by Suppressing NLRP3 Inflammasome Activation and Mitochondrial DNA Synthesis

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2138 ◽  
Author(s):  
Hye Eun Lee ◽  
Gabsik Yang ◽  
Youn Bum Park ◽  
Han Chang Kang ◽  
Yong-Yeon Cho ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Dna Synthesis ◽  
Nlrp3 Inflammasome ◽  
De Novo ◽  
Inflammasome Activation ◽  
Acute Gout ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Mitochondrial Dna Synthesis ◽  
Msu Crystals

Gout is a chronic inflammatory disease evoked by the deposition of monosodium urate (MSU) crystals in joint tissues. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is responsible for the gout inflammatory symptoms induced by MSU crystals. We investigated whether epigallocatechin-3-gallate (EGCG) suppresses the activation of the NLRP3 inflammasome, thereby effectively preventing gouty inflammation. EGCG blocked MSU crystal-induced production of caspase-1(p10) and interleukin-1β in primary mouse macrophages, indicating its suppressive effect on the NLRP3 inflammasome. In an acute gout mouse model, oral administration of EGCG to mice effectively alleviated gout inflammatory symptoms in mouse foot tissue injected with MSU crystals. The in vivo suppressive effects of EGCG correlated well with the suppression of the NLRP3 inflammasome in mouse foot tissue. EGCG inhibited the de novo synthesis of mitochondrial DNA as well as the production of reactive oxygen species in primary mouse macrophages, contributing to the suppression of the NLRP3 inflammasome. These results show that EGCG suppresses the activation of the NLRP3 inflammasome in macrophages via the blockade of mitochondrial DNA synthesis, contributing to the prevention of gouty inflammation. The inhibitory effects of EGCG on the NLRP3 inflammasome make EGCG a promising therapeutic option for NLRP3-dependent diseases such as gout.

scholarly journals Plasma-borne indicators of inflammasome activity in Parkinson’s disease patients

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Faith L. Anderson ◽  
Katharine M. von Herrmann ◽  
Angeline S. Andrew ◽  
Yuliya I. Kuras ◽  
Alison L. Young ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Inflammasome Activation ◽  
Membrane Pore ◽  
Related Proteins ◽  
Inflammasome Activity

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related “speck” formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.

scholarly journals The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Elisa Benetti ◽  
Fausto Chiazza ◽  
Nimesh S. A. Patel ◽  
Massimo Collino
Keyword(s):  
Chronic Inflammation ◽  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Metabolic Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Leucine Rich Repeat Protein

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1βand IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

scholarly journals ANXA3 regulates HIF1α-induced NLRP3 inflammasome activity and promotes LPS-induced inflammatory response in bronchial epithelial cells

2021 ◽  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Response ◽  
Nlrp3 Inflammasome ◽  
Hypoxia Inducible Factor ◽  
Bronchial Epithelial Cells ◽  
Inflammasome Activation ◽  
Bronchial Epithelial ◽  
Asthmatic Patients ◽  
Pediatric Diseases ◽  
Inflammasome Activity

Introduction: Childhood asthma is one of the most common pediatric diseases, and its incidence is increasing. Annexin A3 (ANXA3) is a member of the Annexin family, a well-known polygenic family of membrane binding proteins. Bioinformation analysis showed that ANXA3 was highly expressed in asthmatic patients, suggesting the effects of ANXA3 on asthma, whereas the mechanism is still unclear. Methods: A inflammatory response model of bronchial epithelial BEAS-2B cells induced by LPS was constructed. Immunoblot and quantitative PCR assays were performed to detect the expression levels of ANXA3 in control or LPS-induced BEAS-2B cells. MTT, flow cytometry (FCM), and Immunoblot assays were respectively conducted to detect the effects of ANXA3 on survival and apoptosis of LPS-induced BEAS-2B cells. qPCR and ELISA assays were performed to detect the expression of TNF-α, IL-6, and IL-8. Additionally, Immunoblot assays were performed to detect the effects of ANXA3 on HIF1α and NLRP3 inflammasome in BEAS-2B cells. Results: We found ANXA3 was overexpressed in LPS-induced BEAS-2B cells. ANXA3 ablation promoted the survival of LPS-induced BEAS-2B cells and suppressed the inflammatory response of LPS-induced BEAS-2B cells. Importantly, we noticed ANXA3 inhibited HIF1α-induced NLRP3 inflammasome activity, and increasing the expression of HIF-α rescued the effects of ANXA3 depletion on asthma. Conclusion: ANXA3 enhanced LPS-triggered inflammation of human bronchial epithelial cells by regulating hypoxia-inducible factor-1α (HIF1α)-mediated NLRP3 inflammasome activation, and thought ANXA3 as a promising molecular target for acute asthma treatment.

scholarly journals Gasdermin D mediates inflammation-induced defects in reverse cholesterol transport and promotes atherosclerosis.

2021 ◽  
Author(s):  
Emmanuel Opoku ◽  
Cynthia Alicia Traughber ◽  
David Zhang ◽  
Amanda J Iacano ◽  
Mariam Khan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Reverse Cholesterol Transport ◽  
Foam Cell ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Cholesterol Transport ◽  
Inflammasome Activation ◽  
Lesion Area ◽  
Direct Role

Nlrp3 inflammasome is activated in advanced human atherosclerotic plaques. Gasdermin D (GsdmD) serves as a final executor of Nlrp3 inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-b). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1b; antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/IL-1b; nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet clear. Here, we used in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release ~80% less IL-1b; vs WT mice. The GsdmD-/- macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ~26% decrease vs. ~60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1b; dependent fashion. The GsdmD-/- mice were resistance to Nlrp3 inflammasome mediated defect in RCT, with ~32% reduction in plasma RCT vs. ~ 57% reduction in WT mice, ~ 17% reduction in RCT to liver vs. 42% in WT mice, and ~ 37% decrease in RCT to feces vs. ~ 61% in WT mice. The LDLr anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed role of GsdmD in promoting atherosclerosis. The GsdmD-/- mice exhibit ~42% decreased atherosclerotic lesion area in females and ~33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing WT mice showed the presence of cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD during atherosclerosis. Our data show that GsdmD mediates inflammation-induced defect in RCT and promotes atherosclerosis.

scholarly journals The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing M1 macrophage polarization in mice

Blood ◽  
2020 ◽  
Vol 136 (4) ◽  
pp. 501-515 ◽  
Author(s):  
Kunpeng Wu ◽  
Yan Yuan ◽  
Huihui Yu ◽  
Xin Dai ◽  
Shu Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Macrophage Polarization ◽  
Short Chain Fatty Acids ◽  
Inflammasome Activation ◽  
Microbial Metabolites ◽  
M1 Macrophage ◽  
The Impact

Abstract The diversity of the human microbiome heralds the difference of the impact that gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease (GVHD), even though short-chain fatty acids and indole were demonstrated to reduce its severity. In this study, we dissected the role of choline-metabolized trimethylamine N-oxide (TMAO) in the GVHD process. Either TMAO or a high-choline diet enhanced the allogenic GVH reaction, whereas the analog of choline, 3,3-dimethyl-1-butanol reversed TMAO-induced GVHD severity. Interestingly, TMAO-induced alloreactive T-cell proliferation and differentiation into T-helper (Th) subtypes was seen in GVHD mice but not in in vitro cultures. We thus investigated the role of macrophage polarization, which was absent from the in vitro culture system. F4/80+CD11b+CD16/32+ M1 macrophage and signature genes, IL-1β, IL-6, TNF-α, CXCL9, and CXCL10, were increased in TMAO-induced GVHD tissues and in TMAO-cultured bone marrow–derived macrophages (BMDMs). Inhibition of the NLRP3 inflammasome reversed TMAO-stimulated M1 features, indicating that NLRP3 is the key proteolytic activator involved in the macrophage’s response to TMAO stimulation. Consistently, mitochondrial reactive oxygen species and enhanced NF-κB nuclear relocalization were investigated in TMAO-stimulated BMDMs. In vivo depletion of NLRP3 in GVHD recipients not only blocked M1 polarization but also reversed GVHD severity in the presence of TMAO treatment. In conclusion, our data revealed that TMAO-induced GVHD progression resulted from Th1 and Th17 differentiation, which is mediated by the polarized M1 macrophage requiring NLRP3 inflammasome activation. It provides the link among the host choline diet, microbial metabolites, and GVH reaction, shedding light on alleviating GVHD by controlling choline intake.

scholarly journals The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development

2020 ◽  
Vol 295 (24) ◽  
pp. 8325-8330 ◽  
Author(s):  
Sannula Kesavardhana ◽  
R. K. Subbarao Malireddi ◽  
Amanda R. Burton ◽  
Shaina N. Porter ◽  
Peter Vogel ◽  
...  
Keyword(s):  
Cell Death ◽  
Nucleic Acids ◽  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Defense Responses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Perinatal Lethality

Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1ΔZα2/ΔZα2 mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus–induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (Ripk1mRHIM/mRHIM). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus–induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1mRHIM/mRHIM mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.

scholarly journals Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

2020 ◽  
Vol 21 (14) ◽  
pp. 5097
Author(s):  
Aleksandar Arsenijevic ◽  
Bojana Stojanovic ◽  
Jelena Milovanovic ◽  
Dragana Arsenijevic ◽  
Nebojsa Arsenijevic ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Animal Studies ◽  
Current Knowledge ◽  
Specific Binding ◽  
Primary Biliary Cholangitis ◽  
Inflammasome Activation ◽  
Multimeric Complex ◽  
Galectin 3 ◽  
Binding Lectin

Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development.

scholarly journals The role of NLRP3 inflammasome activation in radiation damage

2019 ◽  
Vol 118 ◽  
pp. 109217 ◽  
Author(s):  
Jinlong Wei ◽  
Heru Wang ◽  
Huanhuan Wang ◽  
Bin Wang ◽  
Lingbin Meng ◽  
...  
Keyword(s):  
Radiation Damage ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation
Sign in / Sign up

Export Citation Format

Share Document