NLRP3 inflammasome activation results in liver inflammation and fibrosis in mice infected with Schistosoma japonicum in a Syk-dependent manner

Conjugated polyenes are a class of widely occurring natural products with various biological functions. We previously identified 4-hydroxy auxarconjugatin B (4-HAB) as anti‐inflammatory agent with an IC50 of ~20 µM. In this study, we synthesized a new anti‐inflammatory 4-HAB analogue, F240B, which has an IC50 of less than 1 µM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibited NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome activation through autophagy induction. In a mechanistic study, F240B inhibited interleukin (IL)-1β (IL-1β) precursor expression, promoted degradation of NLRP3 and IL-1β, and reduced mitochondrial membrane integrity loss in an autophagy-dependent manner. Additionally, F240B inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation without affecting the interaction between NLRP3 and ASC or NIMA-related kinase 7 (NEK7) and double-stranded RNA-dependent kinase (PKR). Furthermore, F240B exerted in vivo anti-inflammatory activity by reducing the intraperitoneal influx of neutrophils and the levels of IL-1β, active caspase-1, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in lavage fluids in a mouse model of uric acid crystal-induced peritonitis. In conclusion, F240B attenuated the NLRP3 inflammasome through autophagy induction and can be developed as an anti-inflammatory agent in the future.

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Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner

Pharmacological Research ◽

10.1016/j.phrs.2015.05.012 ◽

2015 ◽

Vol 99 ◽

pp. 101-115 ◽

Cited By ~ 53

Author(s):

Yi Li ◽

Jie Yang ◽

Mei-Hong Chen ◽

Qiang Wang ◽

Min-Jian Qin ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Endoplasmic Reticulum Stress ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Dependent Manner ◽

Nlrp3 Inflammasome Activation

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Different bile acids display distinct ability to trigger Nlrp3 inflammasome activation in a cell-dependent manner contributing to cholestatic liver injury and fibrosis

Journal of Hepatology ◽

10.1016/s0168-8278(18)31144-9 ◽

2018 ◽

Vol 68 ◽

pp. S451

Author(s):

M. Inzaugarat ◽

T.M. Holtmann ◽

M. Frissen ◽

L.J. Geisler ◽

J. Reissing ◽

...

Keyword(s):

Liver Injury ◽

Bile Acids ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Dependent Manner ◽

Nlrp3 Inflammasome Activation ◽

A Cell ◽

Cholestatic Liver Injury

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DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation

Frontiers in Immunology ◽

10.3389/fimmu.2021.653883 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ioannis Kienes ◽

Sarah Bauer ◽

Clarissa Gottschild ◽

Nora Mirza ◽

Jens Pfannstiel ◽

...

Keyword(s):

Innate Immunity ◽

Nlrp3 Inflammasome ◽

Inflammatory Cytokine ◽

Inflammasome Activation ◽

Type I ◽

Dependent Manner ◽

Type I Ifn ◽

Central Target ◽

Nlrp3 Inflammasome Activation ◽

Lrr Domain

Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. The human Nod-like receptor (NLR) NLRP11 has been shown to regulate type I IFN and pro-inflammatory cytokine responses. Here, we identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11, using co-immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKϵ-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the LRR domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.

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Intra-articular Injection of Baicalein Inhibits Cartilage Catabolism and NLRP3 Inflammasome Signaling in a Posttraumatic OA Model

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6116890 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Hui Bai ◽

Rui Yuan ◽

Zhiheng Zhang ◽

Lin Liu ◽

Xinyu Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Rat Model ◽

Nlrp3 Inflammasome ◽

Type Ii Collagen ◽

Cartilage Degeneration ◽

Inflammasome Activation ◽

Dependent Manner ◽

Nlrp3 Inflammasome Activation ◽

Immunochemical Staining

Baicalein has been shown to have chondroprotective potential in vitro. However, its effect on disease modification in osteoarthritis (OA) is largely unknown. The present study is aimed at determining whether baicalein could slow the progression of OA and inhibit OA-related inflammation in a rat model of destabilization of the medial meniscus (DMM) and the underlying mechanisms. The rats subjected to DMM surgery were treated with baicalein (0.8, 1.6, and 3.2 μg/L, 50 μL, once a week) by intra-articular injection for 6 weeks. Dexamethasone (0.4 mg/mL, 50 μL, once a week) was used as a positive control. Histologic grading of cartilage degeneration was performed using the Osteoarthritis Research Society International (OARSI) recommended grading system (on a scale of 0-6). The expression levels of molecules associated with cartilage homeostasis and inflammatory cytokines were analyzed; moreover, the NLRP3 inflammasome activation and cartilage oxidative stress-associated molecules were determined. Baicalein treatment reduced the OARSI score and slowed OA disease progression in a dose-dependent manner within a certain range. Compared with DMM rats, intra-articular injection of baicalein led to (1) reduced levels of inflammatory mediates such as IL-1β and TNF-α, (2) reduced immunochemical staining of MMP-13 and ADAMTS-5, (3) suppressed immunochemical staining loss of type II collagen, (4) reduced expression of cartilage degradation markers including CTX-II and COMP in urine, and (5) inhibited NLRP3 inflammasome activation rather than regulated expression of SOD, GSH, and MDA. In contrast to the administration of baicalein, dexamethasone injection showed similar effects to slow OA progression, while dexamethasone inhibited NLRP3 inflammasome partly through decreasing levels of SOD, GSH, and MDA. This study indicated that baicalein may have the potential for OA prevention and exerts anti-inflammatory effects partly via suppressing NLRP3 inflammasome activation without affecting oxidative stress-associated molecules, and inhibition of cartilage catabolism enzymes in an OA rat model.

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Calycosin Alleviates Doxorubicin-Induced Cardiotoxicity and Pyroptosis by Inhibiting NLRP3 Inflammasome Activation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/1733834 ◽

2022 ◽

Vol 2022 ◽

pp. 1-15

Author(s):

Lei Zhang ◽

Cundong Fan ◽

Hua-Chen Jiao ◽

Qian Zhang ◽

Yue-Hua Jiang ◽

...

Keyword(s):

Nlrp3 Inflammasome ◽

Cardiac Injury ◽

H9c2 Cell ◽

Inflammasome Activation ◽

Dependent Manner ◽

H9c2 Cells ◽

Stress Injury ◽

Nlrp3 Inflammasome Activation

Calycosin (CAL) is the main active component present in Astragalus and reportedly possesses diverse pharmacological properties. However, the cardioprotective effect and underlying mechanism of CAL against doxorubicin- (DOX-) induced cardiotoxicity need to be comprehensively examined. Herein, we aimed to investigate whether the cardioprotective effects of CAL are related to its antipyroptotic effect. A cardiatoxicity model was established by stimulating H9c2 cells and C57BL/6J mice using DOX. In vitro, CAL increased H9c2 cell viability and decreased DOX-induced pyroptosis via NLRP3, caspase-1, and gasdermin D signaling pathways in a dose-dependent manner. In vivo, CAL-DOX cotreatment effectively suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis via the same molecular mechanism. Next, we used nigericin (Nig) and NLRP3 forced overexpression to determine whether CAL imparts antipyroptotic effects by inhibiting the NLRP3 inflammasome in vitro. Furthermore, CAL suppressed DOX-induced mitochondrial oxidative stress injury in H9c2 cells by decreasing the generation of reactive oxygen species and increasing mitochondrial membrane potential and adenosine triphosphate. Likewise, CAL attenuated the DOX-induced increase in malondialdehyde content and decreased superoxide dismutase and glutathione peroxidase activities in H9c2 cells. In vivo, CAL afforded a protective effect against DOX-induced cardiac injury by improving myocardial function, inhibiting brain natriuretic peptide, and improving the changes of the histological morphology of DOX-treated mice. Collectively, our findings confirmed that CAL alleviates DOX-induced cardiotoxicity and pyroptosis by inhibiting NLRP3 inflammasome activation in vivo and in vitro.

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