scholarly journals Rab GTPase Mediating Regulation of NALP3 in Colorectal Cancer

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4834
Author(s):  
Gülçin Tezcan ◽  
Ekaterina E. Garanina ◽  
Margarita N. Zhuravleva ◽  
Shaimaa Hamza ◽  
Albert A. Rizvanov ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Vesicle Trafficking ◽  
Magnetic Bead ◽  
Dominant Negative ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Caspase 1

The NALP3 inflammasome signaling contributes to inflammation within tumor tissues. This inflammation may be promoted by the vesicle trafficking of inflammasome components and cytokines. Rab5, Rab7 and Rab11 regulate vesicle trafficking. However, the role of these proteins in the regulation of inflammasomes remains largely unknown. To elucidate the role of these Rab proteins in inflammasome regulation, HCT-116, a colorectal cancer (CRC) cell line expressing pDsRed-Rab5 wild type (WT), pDsRed-Rab5 dominant-negative (DN), pDsRed-Rab7 WT, pDsRed-Rab7 DN, pDsRed-Rab11 WT and pDsRed-Rab11 DN were treated with lipopolysaccharide (LPS)/nigericin. Inflammasome activation was analyzed by measuring the mRNA expression of NLRP3, Pro-CASP1, RAB39A and Pro-IL-1β, conducting immunofluorescence imaging and western blotting of caspase-1 and analysing the secretion levels of IL-1β using enzyme-linked immunosorbent assay (ELISA). The effects of Rabs on cytokine release were evaluated using MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel-Premixed 41 Plex. The findings showed that LPS/nigericin-treated cells expressing Rab5-WT indicated increased NALP3 expression and secretion of the IL-1β as compared to Rab5-DN cells. Caspase-1 was localized in the nucleus and cytosol of Rab5-WT cells but was localized in the cytosol in Rab5-DN cells. There were no any effects of Rab7 and Rab11 expression on the regulation of inflammasomes. Our results suggest that Rab5 may be a potential target for the regulation of NALP3 in the treatment of the CRC inflammation.

scholarly journals Rab11A Controls the Biogenesis of Birbeck Granules by Regulating Langerin Recycling and Stability

2007 ◽  
Vol 18 (8) ◽  
pp. 3169-3179 ◽  
Author(s):  
Stéphanie Uzan-Gafsou ◽  
Huguette Bausinger ◽  
Fabienne Proamer ◽  
Solange Monier ◽  
Dan Lipsker ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Rab Gtpase ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Interacting Proteins ◽  
Endocytic Recycling ◽  
Dynamic Regulation ◽  
Birbeck Granules ◽  
Endosomal Recycling

The extent to which Rab GTPases, Rab-interacting proteins, and cargo molecules cooperate in the dynamic organization of membrane architecture remains to be clarified. Langerin, a recycling protein accumulating in the Rab11-positive compartments of Langerhans cells, induces the formation of Birbeck granules (BGs), which are membrane subdomains of the endosomal recycling network. We investigated the role of Rab11A and two members of the Rab11 family of interacting proteins, Rip11 and RCP, in Langerin traffic and the biogenesis of BGs. The overexpression of a dominant-negative Rab11A mutant or Rab11A depletion strongly influenced Langerin traffic and stability and the formation of BGs, whereas modulation of other Rab proteins involved in dynamic regulation of the endocytic-recycling pathway had no effect. Impairment of Rab11A function led to a missorting of Langerin to lysosomal compartments, but inhibition of Langerin degradation by chloroquine did not restore the formation of BGs. Loss of RCP, but not of Rip11, also had a modest, but reproducible effect on Langerin stability and BG biogenesis, pointing to a role for Rab11A–RCP complexes in these events. Our results show that Rab11A and Langerin are required for BG biogenesis, and they illustrate the role played by a Rab GTPase in the formation of a specialized subcompartment within the endocytic-recycling system.

scholarly journals Rabeprazole inhibits inflammatory reaction by inhibition of cell pyroptosis in gastric epithelial cells

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jing Xie ◽  
Long Fan ◽  
Liya Xiong ◽  
Peiyu Chen ◽  
Hongli Wang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Clinical Sample ◽  
Critical Role ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Peptic Ulcers ◽  
Gastric Epithelial Cells ◽  
Caspase 1 ◽  
H Pylori

Abstract Background Helicobacter pylori (H. pylori) is a common pathogen in development of peptic ulcers with pyroptosis. Rabeprazole, a critical component of standard triple therapy, has been widely used as the first-line regimen for H. pylori infectious treatment. The aim of this study to explore the function of Rabeprazole on cell pyroptosis in vitro. Methods The clinical sample from patients diagnosed with or without H. pylori-infection were collected to analyze by Immunohistochemistry (IHC). Real-time quantitative PCR (qPCR), western blot (WB) and enzyme linked immunosorbent assay (Elisa) were performed to analyze the effect of Rabeprazole on cell pyroptosis, including LDH, IL-1β and IL-18. Results In this study, we showed that Rabeprazole regulated a phenomenon of cell pyroptosis as confirmed by lactate dehydrogenase (LDH) assay. Further results showed that Rabeprazole inhibited cell pyroptosis in gastric epithelial cells by alleviating GSDMD-executed pyroptosis, leading to decrease IL-1β and IL-18 mature and secretion, which is attributed to NLRP3 inflammasome activation inhibition. Further analysis showed that ASC, NLRP3 and Caspase-1, was significantly repressed in response to Rabeprazole stimulation, resulting in decreasing cleaved-caspase-1 expression. Most important, NLRP3 and GSDMD is significantly increased in gastric tissue of patients with H. pylori infection. Conclusion These findings revealed a critical role of Rabeprazole in cell pyroptosis in patients with H. pylori infection, suggesting that targeting cell pyroptosis is an alternative strategy in improving H. pylori treatment.

scholarly journals miR-29a-5p Alleviates Traumatic Brain Injury (TBI)-Induced Permeability Disruption Via Regulating NLRP3 Pathway

2021 ◽  
Author(s):  
Aijun Zhang ◽  
Youming Lu ◽  
Lei Yuan ◽  
Pengqi Zhang ◽  
Dongdong Zou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Endothelial Cell ◽  
Brain Injury ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Promising Strategy ◽  
Pathway Activation ◽  
Nlrp3 Expression

Abstract Blood-brain barrier (BBB) dysfunction is presented during traumatic brain injury (TBI) and is dependent upon the activation of the NLRP3/Caspase-1 inflammasome pathway. MicroRNA (miRNA) was proved to inhibit signaling pathway activation by targeting gene expression and we predicated in the database that miR-29a targets to NLRP3. Herein, this study aims to define the regulating role of miR-29a in NLRP3 expression and NLRP3/Caspase-1 inflammasome activation in TBI-induced BBB dysfunction. Our results indicated that miR-29a-5p alleviates TBI-induced the increased permeability of endothelial cell and BBB via suppressing NLRP3 expression and NLRP3/Caspase-1 inflammasome activation, providing a promising strategy for relieving TBI via inhibiting NLRP3/Caspase-1 inflammasome activation.

scholarly journals Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD

2018 ◽  
Vol 29 (4) ◽  
pp. 1165-1181 ◽  
Author(s):  
Takanori Komada ◽  
Hyunjae Chung ◽  
Arthur Lau ◽  
Jaye M. Platnich ◽  
Paul L. Beck ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Inflammasome Activation ◽  
Dna Uptake ◽  
Chronic Injury ◽  
Caspase 1 ◽  
Double Stranded Dna ◽  
Molecular Pattern ◽  
Macrophage Uptake

Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim2 deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1β cleavage in Aim2−/− or WT mice that received WT bone marrow than in WT mice that received Aim2−/− bone marrow. Intravital microscopy of the kidney in LysM(gfp/gfp) mice 5–6 days after UUO demonstrated the significant recruitment of GFP+ proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX3CR1+ renal phagocytes. In vitro, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1β, as well as the formation of AIM2+ ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1β levels, confirming that DNA was the principal damage-associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney.

scholarly journals The signaling adaptor BCAP inhibits NLRP3 and NLRC4 inflammasome activation in macrophages through interactions with Flightless-1

2019 ◽  
Vol 12 (581) ◽  
pp. eaau0615 ◽  
Author(s):  
Samuel J. Carpentier ◽  
Minjian Ni ◽  
Jeffrey M. Duggan ◽  
Richard G. James ◽  
Brad T. Cookson ◽  
...  
Keyword(s):  
B Cell ◽  
Yersinia Pseudotuberculosis ◽  
Cell Receptor ◽  
Pi3k Pathway ◽  
Inflammasome Activation ◽  
Interacting Protein ◽  
Caspase 1 ◽  
B Cell Receptor Signaling ◽  
Phosphoinositide 3 Kinase

B cell adaptor for phosphoinositide 3-kinase (PI3K) (BCAP) is a signaling adaptor that activates the PI3K pathway downstream of B cell receptor signaling in B cells and Toll-like receptor (TLR) signaling in macrophages. BCAP binds to the regulatory p85 subunit of class I PI3K and is a large, multidomain protein. We used proteomic analysis to identify other BCAP-interacting proteins in macrophages and found that BCAP specifically associated with the caspase-1 pseudosubstrate inhibitor Flightless-1 and its binding partner leucine-rich repeat flightless-interacting protein 2. Because these proteins inhibit the NLRP3 inflammasome, we investigated the role of BCAP in inflammasome function. Independent of its effects on TLR priming, BCAP inhibited NLRP3- and NLRC4-induced caspase-1 activation, cell death, and IL-1β release from macrophages. Accordingly, caspase-1–dependent clearance of a Yersinia pseudotuberculosis mutant was enhanced in BCAP-deficient mice. Mechanistically, BCAP delayed the recruitment and activation of pro–caspase-1 within the NLRP3/ASC preinflammasome through its association with Flightless-1. Thus, BCAP is a multifunctional signaling adaptor that inhibits key pathogen-sensing pathways in macrophages.

scholarly journals Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

2021 ◽  
Author(s):  
Elham Kalantari ◽  
Roya Ghods ◽  
Leili Saeednejad Zanjani ◽  
Mandana Rahimi ◽  
Leila Eini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Polyclonal Antibody ◽  
Prognostic Significance ◽  
Rank Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Disease Specific Survival ◽  
Cytoplasmic Expression ◽  
Advanced Tumor ◽  
Disease Specific

Abstract Background: Oncogenic role of doublecortin-like kinase 1 (DCLK1) as a putative cancer stem cell (CSC) marker has been clarified in colorectal cancer (CRC). Isoform-specific function of DCLK1 has highlighted key role of the DCLK1-S (short isoform) in tumor maintenance, progression, and invasion. Considering the lack of commercial anti-DCLK1-S antibody suitable for immunohistochemical (IHC) application, this study was conducted to produce and validate an anti-DCLK1-S polyclonal antibody in order to specifically evaluate expression pattern and clinical significance of short isoform of DCLK1 in colorectal cancer tissues.Methods: Rabbit immunization was performed against a synthetic peptide corresponding to the published six specific amino acid sequences of DCLK1-S, and production of antibody was evaluated by enzyme-linked immunosorbent assay (ELISA). After IHC assessment of the purified anti-DCLK1-S polyclonal antibody, it was used to undertake a definitive study for determining prognostic significance of DCLK1-S expression in a well-defined tissue microarray (TMA) series including 348 CRC and 51 adjacent normal tissues with a follow-up period of 108 months. Results: Positive immunoreactivity of DCLK1-S was found in 84.2% of CRC samples. Cytoplasmic expression was the main localization of DCLK1-S compared to nuclear and membranous area of tumor cells. Expression of DCLK1-S in CRC samples was significantly higher compared to adjacent normal samples (P <0.001). A positive significant association was found between high cytoplasmic expression of DCLK1-S and advanced tumor, nodes, and metastases (TNM) stage (P<0.001) as well as the increased tumor differentiation (P= 0.02). Moreover, the patients with CRC whose tumors showed higher cytoplasmic expression of DCLK1-S had worse disease-specific survival (DSS) (log-rank test, P = 0.03) and 5-year DSS rate (P= 0.01). Additionally, the improved prognostic value was seen in the patients with CRC with high DCLK1-S expression versus moderate expression (HR: 2.70, 95% CI: 0.98-7.38; p =0.04) by multivariate analysis.Conclusions: Our findings strongly supported that DCLK1-S isoform may play a crucial role in invasion, tumor aggressive behavior, and worsened DSS of the patients with CRC. Importantly, high cytoplasmic expression of DCLK1-S compared to moderate expression could be considered as an independent prognostic factor influencing DSS. Taken together, DCLK1-S can be a candidate as a promising prognostic and targeted-therapeutic indicator for effective treatment of CRC.

Abstract 127: Txnip-Mediated NLRP3 Inflammasome Activation as a Novel Mechanism of Myocardial Ischemia-Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yi Liu ◽  
Lijian Zhang ◽  
Yan Qu ◽  
Chao Gao ◽  
Jingyi Liu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Inflammasome Activation ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Myocardial Ischemia Reperfusion

As an inhibitor of the antioxidant thioredoxin, thioredoxin-interacting protein (Txnip) is linked to insulin resistance. NLRP3 inflammasome, a major regulator of innate immunity, has been reported to be activated by Txnip, thus contributing to the pathogenesis of type 2 diabetes mellitus. However, the role of Txnip and its NLRP3 inflammasome activation in the myocardial ischemia/reperfusion (MI/R) injury has not been previously investigated. C57BL/6J mice were subjected to 30 min of ischemia and 3 or 24 hrs of reperfusion. The ischemic heart exhibited increased Txnip and NLRP3 expressions, increased interaction between Txnip and NLRP3 (by immunoprecipitation, 1.8-fold increase over sham), and increased IL-1β, IL-18 and caspase-1 expressions (%increase: 80%, 77% and 110%, respectively) (n=8, all P <0.05). Compared with vehicle group, those mice either receiving intramyocardial small-interfering RNA (siRNA) injection to specifically knockdown the myocardial NLRP3 or intraperitoneal injection of the inflammasome inhibitor (BAY 11-7082) exhibited significantly improved cardiac function (by 28% and 25%), decreased the infarct size (by 40% and 38%), and decreased the cardiomyocytes apoptosis (all P <0.05). NLRP3 knockdown or inflammasome inhibitor also decreased the inflammatory cells infiltration (macrophages and neutrophils) and cytokines (TNF-α, INF-γ and IL-6) production (all P <0.05). To elucidate the role of Txnip in the NLRP3 activation in MI/R, intramyocardial injection of Txnip siRNA was performed to specifically knockdown the myocardial Txnip expression. Compared with vehicle, the Txnip knockdown significantly decreased Txnip/NLRP3 interaction and NLRP3activation as evidenced by lower expressions of IL-1β and caspase-1, decreased inflammatory cells infiltration and cytokines expressions, and consequently decreased the myocardial infarct size and increased the heart function (all P <0.05). Collectively, we demonstrated for the first time that Txnip mediatedNLRP3 inflammasome activation is a novel mechanism of MI/R injury. Interventions targeted to blocking the activation of NLRP3 by inhibiting Txnip may have therapeutic potential for preventing MI/R injury.

NLRP3 inflammasome activation contributes to aldosterone-induced podocyte injury

2017 ◽  
Vol 312 (4) ◽  
pp. F556-F564 ◽  
Author(s):  
Mi Bai ◽  
Ying Chen ◽  
Min Zhao ◽  
Yue Zhang ◽  
John Ci-Jiang He ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Renal Tubules ◽  
Mineralocorticoid Receptor Antagonist ◽  
Podocyte Injury ◽  
Nlrp3 Gene ◽  
Caspase 1 ◽  
Focal Segmental Glomerular Sclerosis ◽  
Nlrp3 Inflammasome Activation

Aldosterone (Aldo) has been shown as an important contributor of podocyte injury. However, the underlying molecular mechanisms are still elusive. Recently, the pathogenic role of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in mediating renal tubular damage was identified while its role in podocyte injury still needs evidence. Thus the present study was undertaken to investigate the role of NLRP3 inflammasome in Aldo-induced podocyte damage. In vitro, exposure of podocytes to Aldo enhanced NLRP3, caspase-1, and IL-18 expressions in dose- and time-dependent manners, indicating an activation of NLRP3 inflammasome, which was significantly blocked by the mineralocorticoid receptor antagonist eplerenone or the antioxidant N-acetylcysteine. Silencing NLRP3 by a siRNA approach strikingly attenuated Aldo-induced podocyte apoptosis and nephrin protein downregulation in line with the blockade of caspase-1 and IL-18. In vivo, since day 5 of Aldo infusion, NLRP3 inflammasome activation and podocyte injury evidenced by nephrin reduction occurred concurrently. More importantly, immunofluorescence analysis showed a significant induction of NLRP3 in podocytes of glomeruli following Aldo infusion. In the mice with NLRP3 gene deletion, Aldo-induced downregulation of nephrin and podocin, podocyte foot processes, and albuminuria was remarkably improved, indicating an amelioration of podocyte injury. Finally, we observed a striking induction of NLRP3 in glomeruli and renal tubules in line with an enhanced urinary IL-18 output in nephrotic syndrome patients with minimal change disease or focal segmental glomerular sclerosis. Together, these results demonstrated an important role of NLRP3 inflammasome in mediating the podocyte injury induced by Aldo.

scholarly journals NLRP3 inflammasome signaling is activated by low-level lysosome disruption but inhibited by extensive lysosome disruption: roles for K+ efflux and Ca2+ influx

2016 ◽  
Vol 311 (1) ◽  
pp. C83-C100 ◽  
Author(s):  
Michael A. Katsnelson ◽  
Kristen M. Lozada-Soto ◽  
Hana M. Russo ◽  
Barbara A. Miller ◽  
George R. Dubyak
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Dominant Negative ◽  
Cell Physiology ◽  
Inflammasome Activation ◽  
Negative Effects ◽  
Murine Bone Marrow ◽  
Caspase 1 ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation

Nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) is a cytosolic protein that nucleates assembly of inflammasome signaling platforms, which facilitate caspase-1-mediated IL-1β release and other inflammatory responses in myeloid leukocytes. NLRP3 inflammasomes are assembled in response to multiple pathogen- or environmental stress-induced changes in basic cell physiology, including the destabilization of lysosome integrity and activation of K+-permeable channels/transporters in the plasma membrane (PM). However, the quantitative relationships between lysosome membrane permeabilization (LMP), induction of increased PM K+ permeability, and activation of NLRP3 signaling are incompletely characterized. We used Leu-Leu- O-methyl ester (LLME), a soluble lysosomotropic agent, to quantitatively track the kinetics and extent of LMP in relation to NLRP3 inflammasome signaling responses (ASC oligomerization, caspase-1 activation, IL-1β release) and PM cation fluxes in murine bone marrow-derived dendritic cells (BMDCs). Treatment of BMDCs with submillimolar (≤1 mM) LLME induced slower and partial increases in LMP that correlated with robust NLRP3 inflammasome activation and K+ efflux. In contrast, supramillimolar (≥2 mM) LLME elicited extremely rapid and complete collapse of lysosome integrity that was correlated with suppression of inflammasome signaling. Supramillimolar LLME also induced dominant negative effects on inflammasome activation by the canonical NLRP3 agonist nigericin; this inhibition correlated with an increase in NLRP3 ubiquitination. LMP elicited rapid BMDC death by both inflammasome-dependent pyroptosis and inflammasome-independent necrosis. LMP also triggered Ca2+ influx, which attenuated LLME-stimulated NLRP3 inflammasome signaling but potentiated LLME-induced necrosis. Taken together, these studies reveal a previously unappreciated signaling network that defines the coupling between LMP, changes in PM cation fluxes, cell death, and NLRP3 inflammasome activation.

scholarly journals Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation

2020 ◽  
Author(s):  
Jianjun Jiang ◽  
Jin Yang ◽  
Yining Shi ◽  
Jiyu Cao ◽  
Youjin Lu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Underlying Mechanism ◽  
Acid Sphingomyelinase ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation

Abstract Background: The NOD-Like Receptor Protein 3 (NLRP3) inflammasome is a crucial component of an array of inflammatory conditions. It functions by boosting the secretion of pro-inflammatory cytokines: interleukin-1β (IL-1β) and interleukin-18 (IL-18). Previous studies have established the vital role of the acid sphingomyelinase (ASM)/ceramide (Cer) pathway in the functional outcome of cells, with a particular emphasis on the inflammatory processes. This study aimed to explore the effects and associated underlying mechanism of Cer-induced NLRP3 inflammasome activation.Methods: Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells was used as an in vitro inflammatory model. Western blotting and Real-time PCR (RT-PCR) were used to detect the protein and mRNA levels, respectively. IL-1β and IL-18 levels were evaluated using ELISA kits. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content.Results: Imipramine, a well-known inhibitor of ASM, significantly inhibited ASM activity and inhibited Cer accumulation, which indicated ASM activation. Besides, it also suppressed the LPS/ATP-induced expression of proteins and mRNA: thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β and IL-18. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced TXNIP/NLRP3 inflammasome activation; however, it did not affect LPS/ATP-induced ASM activation and ceramide production. Further analysis showed that the exogenous C2-Cer treated J774A.1 cells induced the overexpression of TXNIP, NLRP3, caspase-1, IL-1β and IL-18. Besides, TXNIP siRNA or verapamil inhibited C2-Cer-induced TXNIP overexpression and NLRP3 inflammasome activation.Conclusion: This study demonstrated the involvement of the ASM/Cer/TXNIP signaling pathway in NLRP3 inflammasome activation.

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