NLRP3 Inflammasome Activation Research Articles (Page 1)

Platycodin D targets ZNF70 to inhibit NLRP3 inflammasome and STAT3 signaling pathway to ameliorate colitis.

Senkyunolide A alleviates asthma by inhibiting TGF-β/Smad2/3 signaling pathway and NLRP3 inflammasome activation.

NASH exacerbates inflammatory bone destruction and macrophage NLRP3 inflammasome activation in ligature-induced periodontitis.

Background: Sepsis-induced cardiomyopathy (SICM) is a major cause of high morbidity and mortality in septic patients. In SICM, macrophage infiltration and aberrant immune activation play a critical role in triggering inflammatory responses in cardiac tissue. Our previous studies identified that among 23 natural small molecules, Protocatechualdehyde (PCA) exhibited the most potent inhibitory effect on macrophage inflammation. However, the effects of PCA on sepsis-induced cardiac dysfunction remain poorly understood. Research Questions: This study aims to investigate the role of the small molecule PCA in sepsis-induced cardiomyopathy and the underlying potential mechanisms involved. Methods: We established a sepsis mouse model using cecal ligation and puncture (CLP) and treated the mice with intraperitoneal injections of 20 mg/kg and 40 mg/kg of PCA for 5 consecutive days. Heart function was evaluated by measuring survival time, heart function biomarkers, and hemodynamic parameters. Lipopolysaccharide (LPS)-treated mouse bone marrow-derived macrophages (BMDMs) were used to establish a macrophage pyroptosis model. We assessed the activation of NLRP3 inflammasomes, the release of inflammatory cytokines, and gasdermin-D (GSDMD)-mediated mitochondrial pore formation and mitochondrial DNA leakage, and examined their effects on downstream STING/IRF3 signaling pathways. Rusult: The in vivo results of this study demonstrated that PCA significantly alleviated cardiac dysfunction, inflammatory cell infiltration, and the production of inflammatory cytokines in septic mice. Further in vitro experiments showed that PCA inhibited the activation of NLRP3 inflammasome in BMDMs from mice and reduced GSDMD-mediated pyroptosis as well as the activation of the downstream STING/IRF3 pro-inflammatory pathway. Mechanistically, PCA reduced the production of mitochondrial reactive oxygen species (mtROS), thereby inhibiting the activation of the NLRP3 inflammasome and the formation of N-GSDMD. This, in turn, reduced the accumulation of N-GSDMD on both the cell membrane and mitochondrial membrane, further inhibiting the release of mitochondrial DNA (mtDNA) into the cytoplasm. Ultimately, this suppressed the activation of the downstream STING/IRF3 pro-inflammatory pathway, leading to a reduction in the release of inflammatory cytokines. Conclusion: These results highlight the therapeutic role of PCA in the resolution of sepsis-induced cardiac inflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), has become the most common chronic liver disease globally, with its incidence rising annually. MASLD is closely linked to metabolic syndrome and can progress from simple steatosis to more severe stages, including non-alcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), affecting 13%–38.2% of cases. Notably, in 40%–50% of patients, this progression occurs without cirrhosis. The dysregulation of glucose and lipid metabolism is a fundamental pathological mechanism in MASLD and its transition to HCC. Key factors include insulin resistance, increased gluconeogenesis, impaired β-oxidation, oxidative stress, and chronic inflammation, all of which contribute to a tumor-promoting hepatic microenvironment. This review provides a comprehensive analysis of the latest research on MASLD-related HCC, emphasizing disturbances in glucose metabolism (such as disrupted hepatic insulin signaling, key enzymes like G6Pase and PK, and miRNAs such as miR-22-3p that induce Warburg effects), lipid imbalances (for example, upregulation of FASN/ACC and downregulation of PPARα targets like CPT1A), and the crosstalk between various pathways (including mTORC1, AMPK/ACC, FXR, and NF-κB/JNK). It also explores metabolic regulators such as DKK3, FGF21, and O-GlcNAcylation, and examines the role of the gut microbiota in modulating short-chain fatty acids, bile acids, and NLRP3 inflammasome activation in disease progression. By integrating the latest advancements in basic and clinical research, this article presents a solid theoretical framework for early diagnosis, risk assessment, biomarker development, and precision therapies. It also highlights promising therapeutic targets, including PPARα agonists, mTOR inhibitors, FGF21 analogs, and microbiota interventions, while proposing future directions in multi-omics and personalized treatment strategies.

Background: Pericarditis is the inflammation of the pericardial sac, and it has been associated with the activation of the NLRP3 inflammasome, which regulates Interleukin-1β (IL-1β) release. The use of prednisolone (Pred), a potent anti-inflammatory glucocorticoid, has been associated with relapse, and in patients with systemic lupus erythematosus, with increased risk of pericarditis. Hypothesis: We aimed to assess the effects of Pred on the NLRP3 inflammasome activation and IL-1β release in cultured macrophages. We hypothesized that long-term Pred treatment fails to inhibit IL-1β release. Methods: J774A.1 mouse macrophages were primed with lipopolysaccharide (LPS, 1 µg/mL, 6h) to mimic pro-inflammatory conditions, followed by treatment with Pred (10, 1, or 0.1 µM) for 24 h, and then by NLRP3 activation with Adenosine triphosphate (ATP, 5 mM, 30 min). To study the short- and long-term preventive effects of Pred, cells were treated with Pred (10, 1, or 0.1 µM) for 24 hours and 4 weeks, respectively, prior to LPS and ATP. IL-1β concentration was measured by Enzyme-linked immunosorbent assay (ELISA). Results: When administered after LPS, Pred showed a dose-dependent reduction in IL-1β at 24 h (in pg/ml, LPS+ATP 1136±12, Pred 10 µM 299±5, Pred 1 µM 294±7, Pred 0.1 µM 439±6; all p<0.0001, Fig 1A). Similarly, when Pred was administered 24 h prior to LPS, it showed a dose-dependent reduction in IL-1β release (in pg/ml, LPS+ATP 983±2, Pred 10 µM 31±1, Pred 1 µM 57±3, Pred 0.1 µM 402±4; all p<0.0001, Fig 1B). Paradoxically, long-term Pred pre-treatment for 4 weeks significantly increased IL-1β levels at all tested doses (in pg/ml, LPS+ATP 632±78, Pred 10 µM 734±17, Pred 1 µM 923±25, Pred 0.1 µM 763±74; all p<0.01, Fig 1C). Conclusion: Short-term Pred exhibits a dose-dependent inhibitory effect on IL-1β release in macrophages, interfering with inflammasome triggering, whereas long-term exposure to Pred exacerbates IL-1β release. This paradoxical difference in effect may help explain both the loss of efficacy of glucocorticoids over time and the increased recurrence of pericarditis observed in patients undergoing prolonged prednisone therapy. Further studies are warranted to clarify the underlying mechanisms.

Background: The molecular mechanisms underlying colchicine’s benefits after myocardial infarction (MI) remain unclear. This study aimed to investigate the impact of colchicine on the plasma proteome. Methods: Plasma samples were collected from a subset of 203 COLCOT trial participants at baseline and at six months. Proteomic profiling was performed using a targeted multiple-reaction monitoring mass spectrometry assay, while inflammatory biomarkers were quantified using electrochemiluminescence-based multiplex and enzyme-linked immunosorbent assays. The changes from baseline to six months were analyzed using analysis of covariance models adjusted for baseline values either using the original data or log-transformed data, depending on the distribution. The mean percentage reductions by colchicine are presented for in vitro assays and the logarithm of the ratio of LPS+colchicine/LPS were tested against zero. Results: Reductions in the plasma concentrations of interleukin-12p70 (IL-12p70), IL-12/IL-23p40 (p40) subunit, IFN-γ, and IL-17A were observed in the colchicine group compared with the placebo group (adjusted geometric mean % changes of -42.8% vs. 0.4%, p = 0.007 for IL-12p70 and -23.7% vs. -4.1%, p = 0.053 for IFN-γ; adjusted mean changes of -12.8 pg/ml vs. 7.5 pg/ml, p = 0.003 for IL-12/IL-23p40 and -2.1 pg/ml vs. 0.2 pg/ml, p = 0.038 for IL-17A). Decreases over time in plasma IL-6 and IL-1α concentrations also occurred in the colchicine group compared with placebo (adjusted geometric mean % changes of -51.1% vs. -40.8%, p = 0.055 and -18.9% vs. 7.6%, p = 0.052, respectively). These effects were supported by in vitro assays that demonstrated colchicine-induced reductions of secretion of IL-12 (-41.8%, p=0.023), IL-23 (-21.0%, p=0.014) and IL-6 (-46.7%, p<0.001) by lipopolysaccharide-stimulated THP-1 macrophages. The proteomic panel showed that colchicine, compared with placebo, reduced additional inflammation-related biomarkers including alpha-1-acid glycoprotein, complement factor D and lysozyme C (adjusted geometric mean % changes of -35.6% vs. -28.1%, p = 0.026; -13.2% vs. -0.2%, p = 0.020; and -10.8% vs. -3.3%, p = 0.041, respectively). Conclusions: Low-dose colchicine treatment after MI substantially reduced IL-12 and IL-23 signaling, suggesting important effects on Th1 and Th17 inflammatory pathways. The effects of colchicine on IL-6 and IL-1α also demonstrate its effects on NLRP3 inflammasome activity.

Background: Inhibition of IL-1 is a safe and effective treatment of recurrent pericarditis. However, the currently available agents are administered subcutaneously and there are no approved IL-1-directed oral therapies. NEK7 is a key component of the NLRP3 inflammasome, which drives inflammation through release of IL-1. MRT-8102 is a first-in-class oral molecular glue degrader (MGD) designed to selectively eliminate NEK7 and thereby reduce IL-1-mediated inflammation. MRT-8102 therefore offers a novel investigational approach to targeting inflammatory cardiovascular diseases (CVD). Objectives: To evaluate the potential therapeutic activity of MGD-mediated degradation of NEK7 using preclinical models in mice and non-human primates (NHPs). In addition, to assess the impact of NEK7 degradation on NLRP3 inflammasome activation within in vitro and ex vivo systems. Methods: IL-1β response was evaluated in a mouse model of sterile peritonitis, representing acute innate immune activation relevant to CVD. NEK7 levels and NLRP3-driven IL-1β response were measured in PBMCs from NHPs dosed orally with MRT-8102 once a day for 5 days, followed by ex vivo stimulation with LPS and nigericin. In vitro assays with human whole blood from obese donors, as wells as human monocyte-derived macrophages, were used to assess inflammasome assembly and cytokine release. Results: Proteomic and crystallographic studies confirmed that MRT-8102 forms a selective ternary complex with NEK7 and cereblon, with no identified off-target effects. In a mouse peritonitis model, MRT-8102 led to dose-dependent inhibition of IL-1β and TNF-α in peritoneal fluid and plasma, along with reductions in other inflammatory cytokines. In a NHP multi-dose model, MRT-8102 reduced NEK7 levels by 85%, with near-complete suppression of IL-1β ex vivo. In an ex vivo stimulation model using blood from obese human donors (BMI > 30), and similarly in vitro using human monocyte-derived macrophages, MRT-8102 suppressed IL-1β more potently than a benchmark NLRP3 inhibitor. Conclusion: Our studies indicate that MRT-8102 is a potent, selective NEK7 degrader that inhibits NLRP3-driven activity including cytokine release in vivo and in vitro. Therefore, the NEK7-targeting MGD, MRT-8102, holds promise as a novel therapeutic for the treatment of CVD driven by chronic innate immune activation.

To evaluate the protective effects of resveratrol against acute lung injury (ALI) and investigate the potential mechanisms underlying the reactive oxygen species (ROS)-triggered thioredoxin-interacting protein (TXNIP)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway. C57BL/6 mice and J774A.1 cells were selected as the research subjects. Thirty Mice were randomly divided into 5 groups of 6 in each group: control with 0.9% saline, 5 mg/kg lipopolysaccharide (LPS) 24 h, 25 mg/kg resveratrol + 5 mg/kg LPS, 100 mg/kg resveratrol + 5 mg/kg LPS, and 4 mg/kg NLRP3 inhibitor CY-09 + 5 mg/kg LPS. For cell stimulation, cells were pretreated with 5 and 20 µmol/L resveratrol for 2 h, and stimulated with or without 1 µg/mL LPS and 3 mmol/L ATP for 2 h. The antioxidant N-acetyl-L-cysteine (NAC, 2 µmol/L) was used as the positive control group. Hematoxylin and eosin staining was used to evaluate the degree of lung LPS-induced tissue damage, and enzyme-linked immunosorbent assay was used to evaluate the contents of interleukin-1 β (IL-1 β) and IL-18 in the serum and cell supernatant. ROS and malondialdehyde (MDA) levels in the lung tissue were detected using the corresponding kits. Western blotting was used to detect the expressions of TXNIP, high-mobility group box 1 (HMGB1), NLRP3, as well as cysteine-aspartic acid protease 1 (caspase-1) and gasdermin D (GSDMD) along with their cleaved forms in lung tissue. Additionally, reverse transcription quantitative polymerase chain reaction was performed to analyze the expression of related inflammatory cytokines. ROS content was detected using flow cytometry and confocal laser microscopy. Mitochondrial morphological changes were observed using transmission electron microscopy, and HMGB1 expression was detected using immunofluorescence. Resveratrol significantly alleviated LPS-induced lung damage with reduced inflammation, interstitial edema, and leukocyte infiltration (P<0.01). It also decreased serum levels of IL-1 β and IL-18 (P<0.05), while downregulating the expressions of NLRP3, IL-6, and other inflammatory markers at both the protein and mRNA levels (P<0.05). Notably, the higher dose (100 mg/kg) demonstrated a better effect than the lower dose (25 mg/kg). In macrophages, resveratrol reduced IL-1 β and IL-18 following LPS and ATP stimulation, suppressed HMGB1 translocation, and inhibited formation and activation of the NLRP3 inflammasome (P<0.05 or P<0.01). These anti-inflammatory effects were mediated through the suppression ROS accumulation (P<0.01) and mitochondrial dysfunction. Transmission electron microscopy revealed that resveratrol preserved mitochondrial structure, preventing the mitochondrial damage seen in LPS-treated groups (P<0.01). The expressions of cleaved caspase-1, cleaved GSDMD, and cytoplasmic HMGB1 were all reduced following resveratrol treatment (P<0.01). Moreover, resveratrol inhibited dissociation of TXNIP from thioredoxin, blocking subsequent activation of NLRP3 and downstream inflammatory cytokines (P<0.01). Similarly, the higher concentration of resveratrol (20 µ mol/L) exhibited superior efficacy in vitro. Resveratrol can reduce the inflammatory response following ALI and inhibit the activation of NLRP3 inflammasome and the level of HMGB1 in the cytoplasm by inhibiting ROS overproduction.

Gout, a prevalent metabolic disorder driven by hyperuricemia, results in pathological deposition of monosodium urate (MSU) crystals in joints and soft tissues, stimulating intense inflammatory responses with systemic health consequences. Emerging evidence highlights dysregulated bile acid (BA) metabolism as a pivotal contributor to gout pathogenesis. Imbalances in BA influence disease progression through multiple mechanisms (1): modulating hepatic urate production via PPAR-α/XOD signaling (2), regulating immune responses through FXR/TGR5-dependent suppression of NLRP3 inflammasome activation, and (3) shaping the gut microbiota composition, which reciprocally affects uric acid homeostasis and inflammation. Despite these advances, the precise mechanistic networks linking BA dysmetabolism to gout remain incompletely understood. In this review, we systematically synthesizes current knowledge on BA-gout interactions, elucidated how BA disturbances exacerbate disease progression, discussed the factors contributing to metabolic disorders of BAs, and evaluated promising therapeutic strategies targeting BA pathways. For example, FXR antagonists facilitate the synthesis of BA by inhibiting the aberrant activation of FXR. TGR5 agonists suppress inflammation. Probiotics help restore the diversity of the gut microbiota and increase the abundance of beneficial bacteria, including Bifidobacterium and Lactobacillus . Moreover, traditional Chinese medicine works by improving structural disorders of the gut microbiota and activating CYP7A1 to enhance the BA synthesis pathway. By integrating metabolic, immunological, and microbial perspectives, this work provides a framework for developing novel, mechanism-based interventions against gout.

CA-074 methyl ester, an inhibitor of cathepsin B, combined with the calcium channel blocker Nimodipine inhibits NLRP3 inflammasome activation and alleviates the lesions of Alzheimer's disease transgenic mice.

Atraric acid activates the FoxO3a/PINK1/Parkin signaling pathway to suppress chronic intermittent hypoxia-induced cardiac oxidative stress, inflammatory responses, and NLRP3 inflammasome activation.

Mitophagy attenuates pyroptosis in human gingival fibroblasts through inhibition of NLRP3 inflammasome activation.

Atrial fibrillation (AF) represents one of the most common arrhythmias seen clinically and is associated with a significant increase in morbidity and mortality. One of the main contributors to the pathophysiology for the initiation, progression, and persistence of AF is inflammation. Inflammatory infiltrates and increased serum levels of proinflammatory cytokines have been demonstrated in animal models and patients with AF. AF progression is associated with increased levels of these proinflammatory cytokines. Cigarette smoking is associated with an increased risk of AF. Moreover, cigarette smoke is known to increase inflammation and proinflammatory cytokines including interleukin (IL)-1β, IL-18, and tumor necrosis factor-α (TNF-α). Therefore, it is of great clinical importance to elucidate the underlying mechanisms contributing to smoking-induced inflammation in patients with AF. A critical amplifier of inflammation is the NLRP3 inflammasome, which is increased in patients with AF. Here, we identify critical upstream mechanisms leading to NLRP3 inflammasome activation via endoplasmic reticulum stress in atrial tissues from patients with AF and human-induced pluripotent stem cell-atrial cardiomyocytes. These findings reveal important mechanistic insights into possible upstream targets in controlling excessive inflammation due to smoking in patients with AF.NEW & NOTEWORTHY This study demonstrates that atrial fibrillation patients who have had a history of cigarette smoking within the past year exhibit increased inflammation amplified by NLRP3 inflammasome activation and heightened endoplasmic reticulum (ER) stress. Our findings suggest that ER stress acts as an upstream activator of the NLRP3 inflammasome, presenting a potential therapeutic target to mitigate the excessive inflammation observed in patients with AF with smoking exposure.

The activation of NLRP3 inflammasome and its function in anti-infection immunity of largemouth bass (Micropterus salmoides).

Electroacupuncture Prevents Depression via PINK1/Parkin-Driven Suppression of NLRP3 Activation.

Peroxynitrite is key to Cylindrospermopsin-mediated MASLD to MASH progression via triggering TXNIP binding to NLRP3 and subsequent inflammasome activation.

Discovery of novel 8-hydroxyquinoline derivatives as NLRP3 inflammasome inhibitors with therapeutic potential for inflammatory bowel disease.

Orexin A alleviates chronic cerebral hypoperfusion-induced neuroinflammation and cognitive dysfunction by inhibiting the NEK7/NLRP3 pathway.

Isobavachin alleviates hyperuricemia-induced bone loss by GPR35-NLRP3 signal.