The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for various pathogenic and non-pathogenic damage signals and plays a critical role in host defense against pathogens and physiological damage. However, inflammasome activation and its subsequent effects also lead to a variety of inflammatory diseases. In this study, we identified broxyquinoline, an FDA-approved antimicrobial drug, as a effective NLRP3 inflammasome inhibitor. Broxyquinoline suppressed NLRP3 inflammasome-dependent interleukin-1β (IL-1β) release, but did not affect NLRC4 or AIM2 inflammasome activation. Mechanistically, broxyquinoline directly targets Arg165 of NLRP3 protein, thus preventing NEK7-NLRP3 interaction, NLRP3 oligomerization, and ASC speck formation, without affecting the NF-κB pathway. Consequently, broxyquinoline significantly attenuated the progression of monosodium urate (MSU)-induced peritonitis and myelin oligodendrocyte glycoprotein (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE) in murine models. In conclusion, we demonstrated that broxyquinoline directly targets the NLRP3 protein to suppress the activation of NLRP3 inflammasome and provide a promising therapeutic agent for NLRP3 inflammasome-associated diseases.

Neuronal inflammation and apoptosis aggravate the secondary injury after spinal cord injury (SCI). Cathepsin L (CTSL) is a lysosomal cysteine protease with effects on the regulation of inflammation, but its role in SCI remains unclear. The in vivo T10 mouse spinal cord contusion model was established. The results showed that CTSL expression was increased following SCI and then gradually decreased. Moreover, CTSL was mainly expressed in microglia. To detect the function of CTSL, after contusive injury, the mice were immediately injected with lentiviruses carrying CTSL shRNA. The results showed that CTSL depletion promoted functional recovery, accompanied by increased locomotor ability. CTSL deficiency reduced lesion cavity areas by inhibiting neuronal apoptosis and neuroinflammation. Indeed, CTSL deficiency decreased the secretion of TNF-α, IL-6, and MCP-1 and M1 microglia polarization in the spinal cord. CTSL depletion inhibited the expression and assembly of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome. In vitro, CTSL expression was increased in LPS-treated BV2 cells. CTSL silencing repressed LPS-induced M1 polarization, as evidenced by the reduction in TNF-α, IL-6, and MCP-1 expression in the supernatant of BV2 cells. CTSL knockdown induced the downregulation of NLRP3 expression and activation. The inhibition role of CTSL knockdown in microglial inflammation and M1 polarization was reversed by NLRP3 agonist. Collectively, the study suggests that CTSL induces the microglia M1 polarization-mediated inflammation via promoting NLRP3 activation and thereby inhibits functional recovery after SCI.

Although several estrogen receptor β (ERβ) agonists have been reported to alleviate IBD, the pivotal mechanism remains obscure.

To examine the effects and mechanisms of ERβ activation on cytokine/chemokine networks in colitis mice.

Dextran sulfate sodium salt (DSS) and trinitro-benzene-sulfonic acid (TNBS) were used to induce mouse colitis model. Multiple molecular biological methods were employed to evaluate the severity of mouse colitis and the level of cytokine and/or chemokine.

Bioinformatics analysis, ELISA and immunofluorescence results showed that the targeted cytokines and/or chemokines associated with ERβ expression and activation is IL-1β, and the anti-colitis effect of ERβ activation was significantly attenuated by the overexpression of AAV9-IL-1β. Immunofluorescence analysis indicated that ERβ activation led to most evident downregulation of IL-1β expression in colonic macrophages as compared to monocytes and neutrophils. Given the pivotal roles of NLRP3, NLRC4, and AIM2 inflammasome activation in the production of IL-1β, we examined the influence of ERβ activation on inflammasome activity. ELISA and WB results showed that ERβ activation selectively blocked the NLRP3 inflammasome assembly-mediated IL-1β secretion. The calcium-sensing receptor (CaSR) and calcium signaling play crucial roles in the assembly of the NLRP3 inflammasome. WB and immunofluorescence results showed that ERβ activation reduced intracellular CaSR expression and calcium signaling in colonic macrophages. Combination with CaSR overexpression plasmid reversed the suppressive effect of ERβ activation on NLRP3 inflammasome assembly, and counteracting the downregulation of IL-1β secretion.

Our research uncovers that the anti-colitis effect of ERβ activation is accomplished through the reduction of IL-1β levels in colonic tissue, achieved by specifically decreasing CaSR expression in macrophages to lower intracellular calcium levels and inhibit NLRP3 inflammasome assembly-mediated IL-1β production.

The clinical efficacy of mesenchymal stem cell (MSC) therapy for inflammatory bowel disease (IBD) is inconsistent and often fails to match promising preclinical findings. To improve outcome, we compared MSCs isolated from human uterine myometrium (Ut), a readily-available tissue source from a unique immune niche, to bone marrow (BM) MSCs, the most common source, in a murine IBD model with mechanisms underlying differential effects. In this study, human BMMSCs and UtMSCs were intravenously administered to mice with dextran sulfate sodium-induced colitis and evaluated for disease activity, microbiome composition, and cellular immunity. Bioinformatics analyses including patient data were performed to further specify involved mechanisms with subsequent functional validation performed. We found that UtMSC but not BMMSC treatment significantly reversed disease parameters by improving microbiome and reducing mesenteric lymph node IFN-γ and IL-17A-secreting T cells. Transcriptomic analysis revealed UtMSCs had reduced MHC II pathway activation compared to BMMSCs. Functional validation confirmed UtMSCs compared to BMMSCs expressed lower IFN-γ receptors, prevent MHC II-mediated human unstimulated T cell activation, and modulated stimulated T helper (Th) cells away from effector phenotypes while increasing regulatory T cells (Tregs) and IL-10 levels. Bioinformatics from IBD patients resistant to non-T cell-specific therapies implicated persistent MHC II-mediated Th1/Th17 activation as key drivers of disease. Overall, UtMSCs outperformed BMMSCs in improving microbiota, avoiding IFN-γ responses, and modulating overall Th responses, suggesting this MSC source may offer more significant effectiveness for IBD and Th1/Th17-mediated conditions. Our findings also highlight that understanding MSC source-specific therapeutic mechanisms is crucial for optimizing clinical therapies.

The gut is responsible for the digestion and absorption of nutrients, immune regulation, and barrier function. However, factors like poor diet, stress, and infection, can disrupt the balance of the gut microbiota and lead to intestinal inflammation and dysfunction.

This systematic review aims to evaluate the effects of dietary plants-derived essential oil components on gut health and intestinal functions in animal models.

The literature was gathered from the Scopus, Web of Science, PubMed, and Embase databases by using related search terms, such as "dietary plants", "dietary sources", "essential oils", "gut health", "intestine", "anti-inflammatory", "antioxidant", and "gut microbiota".

The results indicate that plant-derived dietary essential oil components, such as butyrolactone-I, carvacrol, cinnamaldehyde, citral, D-limonene, eugenol, farnesol, geraniol, indole, nerolidol, oleic acid, thymol, trans-anethole, vanillin, α-bisabolol, α-linolenic acid, α-pinene, α-terpineol, β-carotene, β-caryophyllene, and β-myrcene have been found to regulate gut health by influencing vital signalling pathways associated with inflammation. Dietary essential oil components modulate the expression of tumor necrosis factor alpha, interleukin 1 beta (IL-1β), interleukin (IL)-6, IL-10, inducible nitric oxide synthase, cyclooxygenase-2, toll-like receptor-4, matrix metalloproteinase, and interferon gamma in mitigating gut inflammation. The primary signalling molecules controlled by these molecules were AMP-activated protein kinase (AMPK), protein kinase B, extracellular signal-regulated kinase, c-Jun N-terminal kinase, mitogen-activated protein kinase, myeloid differentiation primary response 88, nuclear factor erythroid-2-related factor-2, and phosphoinositide 3-kinase (PI3K). Moreover, these phytochemicals have been shown to improve glucose homeostasis by regulating glucose transporter 4, glucagon-like peptide-1, peroxisome proliferator-activated receptor gamma, nuclear factor kappa B, AMPK, PI3K, and uncoupling protein-1. They can also reduce thiobarbituric acid reactive substance, malondialdehyde, and oxidative stress and enhance superoxide dismutase, catalase, and glutathione peroxidase levels.

In conclusion, dietary plants-derived essential oil components have the potential to mitigate inflammation and oxidative stress in the gut. However, additional clinical investigations are necessary to confirm their complete potential in improving human gut health functions.

This study investigated the protective effects of Garcinia biflavonoid 1 (GB1) against dextran sulfate sodium (DSS)-induced ulcerative colitis and its underlying mechanisms. Using wild-type (WT) and NLRP3 knockout (Nlrp3-/-) mice, we demonstrated that GB1 administration significantly ameliorated colitis symptoms, as evidenced by improved body weight, disease activity index (DAI) scores, colon length, and histological damage in WT mice. Mechanistically, GB1 downregulated pro-inflammatory mediators (IL-6, NF-κB, and CD11b) while attenuating the expression of NLRP3 inflammasome components (ASC, Caspase-1, and IL-1β). Notably, these protective effects were abolished in Nlrp3-/- mice, confirming the essential role of NLRP3 in GB1-mediated mitigation of colitis. Furthermore, GB1 reinforced intestinal barrier integrity by preserving tight junctions, reducing permeability, and attenuating mucosal inflammation. Collectively, our findings highlight GB1 as a promising therapeutic candidate for colitis treatment, primarily through NLRP3 inflammasome suppression and intestinal barrier restoration.

The NOD-like receptor family, particularly the protein 3 that contains the pyrin domain (NLRP3), is an intracellular sensing protein complex responsible for detecting patterns associated with pathogens and injuries. NLRP3 plays a crucial role in the innate immune response. Currently, a wide range of research has indicated the crucial importance of NLRP3 in various inflammatory conditions. Similarly, the NLRP3 inflammasome plays a significant role in preserving intestinal balance and impacting the advancement of diseases. In addition, several randomized trials have demonstrated the safety and efficacy of targeting NLRP3 in the treatment of colitis, colorectal cancer, and related diseases. This review explores the mechanisms of NLRP3 assembly and activation in the gut. We describe its pathological significance in intestinal diseases. Finally, we summarize current and future therapeutic approaches targeting NLRP3 for intestinal diseases.

Inflammatory bowel diseases (IBD) are chronic, remitting, and relapsing conditions of the gastrointestinal tract with incompletely elucidated etiology. The anti-TNF-α mAbs represent one of aflash nanocomplexation and flash nanoprecipitation process, resulting in particles with a narrow size distribution and tunable release profile, with the longest in vitro release lasting over four months. These mAb-releasing NPs are then incorporated into hyaluronic acid hydrogel microparticles (MPs) to enhance tissue retention, thus extending the duration of mAb release in vivo. A single i.m. injection of the LAI can maintain the serum mAb level above the therapeutically effective concentration for over 100 days in healthy mice. In a 9-week study using a dextran sulfate-induced chronic colitis model, the anti-TNF-α LAI formulation demonstrates substantial therapeutic efficacy and a better safety profile than free mAb injections. This work demonstrates the effectiveness of this LAI system in maintaining a persistent serum mAb level and its potential as a versatile, safer, and effective delivery system for antibody therapeutics.

NLRP3 inflammasome is critical in innate immunity and inflammatory responses. A series of novel sulfonylurea-based NLRP3 inflammasome inhibitors was designed and synthesized. Notably, compound 15 exhibited the potent NLRP3 inhibitory activity, effectively suppressing IL-1β secretion in THP-1 (IC50 = 23 nM), demonstrating better efficacy compared to MCC950. It selectively inhibits NLRP3 activation by disrupting inflammasome assembly, with no effect on NLRC4 or AIM2 inflammasomes. Molecular docking showed that the 1-methyl-4-(methylamino)piperidine moiety forms a novel hydrogen bond with Asp662 in the hydrophilic region of NLRP3. Additionally, compound 15 displayed excellent pharmacokinetic properties with 99.6% oral bioavailability in mice. It exhibited superior efficacy in acute peritonitis and diabetic kidney disease models, surpassing MCC950. Tissue distribution studies confirmed that compound 15 specifically targeted the gut and showed efficacy in an IBD model, comparable to MCC950. These findings highlight compound 15 as a promising lead for novel oral NLRP3 inflammasome inhibitors.

Cardiovascular diseases (CVDs) remain a leading cause of global mortality, driven by risk factors such as dyslipidemia, hypertension and diabetes. Recent research has highlighted the critical role of inflammasomes, particularly the NLRP3 inflammasome, in the pathogenesis of various CVDs, including hypertension, atherosclerosis, myocardial infarction and heart failure. Inflammasomes are intracellular protein complexes that activate inflammatory responses through the production of pro-inflammatory cytokines such as IL-1β and IL-18, contributing to endothelial dysfunction, plaque formation and myocardial injury. This review provides a comprehensive overview of the structure, activation mechanisms and pathways of inflammasomes, with a focus on their involvement in cardiovascular pathology. Key activation pathways include ion fluxes (K+ efflux and Ca2+ signalling), endoplasmic reticulum (ER) stress, mitochondrial dysfunction and lysosomal destabilisation. The review also explores the therapeutic potential of targeting inflammasomes to mitigate inflammation and improve outcomes in CVDs. Emerging strategies include small-molecule inhibitors, biologics and RNA-based therapeutics, with a particular emphasis on NLRP3 inhibition. Additionally, the integration of artificial intelligence (AI) in cardiovascular research offers promising avenues for identifying novel biomarkers, predicting disease risk and developing personalised treatment strategies. Future research directions should focus on understanding the interactions between inflammasomes and other immune components, as well as genetic regulators, to uncover new therapeutic targets. By elucidating the complex role of inflammasomes in CVDs, this review underscores the potential for innovative therapies to address inflammation-driven cardiovascular pathology, ultimately improving patient outcomes.

Inflammatory bowel disease (IBD) is an autoimmune disorder primarily characterized by intestinal inflammation and recurrent ulceration, leading to a compromised intestinal barrier and inflammatory infiltration. This disorder's pathogenesis is mainly attributed to extensive damage or death of intestinal epithelial cells, along with abnormal activation or impaired death regulation of immune cells and the release of various inflammatory factors, which contribute to the inflammatory environment in the intestines. Thus, maintaining intestinal homeostasis hinges on balancing the survival and functionality of various cell types. Programmed cell death (PCD) pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, and neutrophil extracellular traps, are integral in the pathogenesis of IBD by mediating the death of intestinal epithelial and immune cells. Natural products derived from plants, fruits, and vegetables have shown potential in regulating PCD, offering preventive and therapeutic avenues for IBD. This article reviews the role of natural products in IBD treatment by focusing on targeting PCD pathways, opening new avenues for clinical IBD management.

This study aimed to investigate the therapeutic potential of scopoletin in ulcerative colitis, with a primary focus on its impact on crucial inflammatory pathways and immune responses. A male mouse model of DSS-induced colitis was employed with six distinct groups: a control group, a group subjected to DSS only, three groups treated with varying scopoletin doses, and the final group treated with dexamethasone. The investigation included an assessment of the effects of scopoletin on colitis symptoms, including alterations in body weight, Disease Activity Index (DAI), and histopathological changes in colonic tissue. Furthermore, this study scrutinized the influence of scopoletin on cytokine production, PPARγ and NF-κB expression, NLRP3 inflammasome, and the composition of intestinal bacteria. Scopoletin treatment yielded noteworthy improvements in DSS-induced colitis in mice, as evidenced by reduced weight loss and colonic shortening (p < 0.05, < 0.01, respectively). It effectively diminished TNF-α, IL-1β, and IL-12 cytokine levels (p < 0.01, p < 0.05), attenuated NLRP3 inflammasome activation and the associated cytokine release (p < 0.05, p < 0.01), and modulated the immune response by elevating PPARγ expression while suppressing NF-κB pathway activation (p < 0.05, p < 0.01). Additionally, scopoletin induced alterations in the gut microbiota composition, augmenting beneficial Lactobacillus and Bifidobacteria while reducing E. coli (p < 0.05). It also enhanced tight junction proteins, signifying an improvement in the intestinal barrier integrity (p < 0.05, < 0.01). Scopoletin is a promising therapeutic agent for managing ulcerative colitis, showing benefits that extend beyond mere anti-inflammatory actions to encompass regulatory effects on gut microbiota and restoration of intestinal integrity.

The NLRP3 inflammasome complex is an important mechanism for regulating the release of pro-inflammatory cytokines, IL-1β and IL-18, in response to harmful pathogens. Overproduction of pro-inflammatory cytokines has been linked to cryopyrin-associated periodic syndrome, arthritis, and other inflammatory conditions. It has been previously shown that tumor progression locus 2, a serine-threonine kinase, promotes IL-1β synthesis in response to LPS stimulation; however, whether TPL2 kinase activity is required during inflammasome priming to promote Il1b mRNA transcription and/or during inflammasome activation for IL-1β secretion remained unknown. In addition, whether elevated type I interferons, a consequence of either Tpl2 genetic ablation or inhibition of TPL2 kinase activity, decreases IL-1β expression or inflammasome function has not been explored. Using LPS-stimulated primary murine bone marrow-derived macrophages, we determined that TPL2 kinase activity is required for transcription of Il1b, but not Nlrp3, Il18, caspase-1 (Casp1), or gasdermin-D (Gsdmd) during inflammasome priming. Both Casp1 and Gsdmd mRNA synthesis decreased in the absence of type I interferon signaling, evidence of crosstalk between type I interferons and the inflammasome. Our results demonstrate that TPL2 kinase activity is differentially required for the expression of inflammasome precursor cytokines and components but is dispensable for inflammasome activation. These data provide the foundation for the further exploration of TPL2 kinase inhibitor as a potential therapeutic in inflammatory diseases.

The activation of inflammasomes (NLRP3 and NLRP1) is central to the pathogenesis of inflammatory bowel disease (IBD). Here we examined the protective effects of a thioredoxin-mimetic peptide CB13 (TXM-CB13), known for its antioxidative stress and anti-inflammatory properties. We examined the effects of TXM-CB13 on dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation in RAW264.7 macrophages. TXM-CB13 appeared to alleviate symptoms of DSS-induced colitis and to significantly suppress the protein and mRNA levels of NLRP3, Mlck, and IL-1β in colonic tissues. Additionally, TXM-CB13 treatment increased the levels of the intestinal barrier proteins Occludin, ZO-1, and NLRP1, as shown through immunohistochemistry and Western blot analysis. In vitro, TXM-CB13 inhibited LPS-induced TLR4 signaling, reducing MyD88 levels and consequently attenuating the activation of the NF-κB pathways, including p-IκB-α/IκB-α and p-NF-κB-p65/NF-κB-p65. This inhibition further reduced the activation of the NLRP3 inflammasome components, NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. In addition, TXM-CB13 prevented the ROS-mediated dissociation of TXNIP from TRX, inhibiting NLRP3 activation. These findings suggest that TXM-CB13 is a potential therapeutic candidate for IBD through its modulation of the TLR4/MyD88/NF-κB/NLRP3 and ROS/TXNIP/TRX/NLRP3 pathways.

G protein-coupled receptors (GPCRs) represent humans' most prominent family of membrane proteins. In contrast, G protein-coupled receptor kinases (GRKs) play a pivotal role in the rapid desensitization of GPCRs. GRK2 is a particularly significant member of the GRK family. Recent studies have demonstrated that GRK2 primarily regulates immune cell function and homeostasis through receptor desensitization. Over the past decade, substantial progress has been made in elucidating the role of GRK2 in various human diseases. Notably, GRK2 is implicated in a range of autoimmune disorders, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), multiple sclerosis (MS), Sjögren's syndrome (SS), autoimmune myocarditis, hepatitis, and Graves' disease. Furthermore, emerging research has expanded our understanding of GRK2's involvement in cancer biology. Comprehensive investigations into the biological and pathological functions of GRK2 have facilitated the development of therapeutic strategies aimed at targeting the GRK2 signaling pathway in cancer, inflammation, and autoimmune diseases. Promising results have been observed with targeted biologics in preclinical and clinical trials. This review aims to elucidate the multifaceted role of GRK2 in immune function, autoimmune diseases, and cancer to uncover the remaining complexities associated with this kinase. A thorough understanding of GRK2 may position it as a potent therapeutic target in treating inflammation and cancer.

Flavonoid is a category of bioactive polyphenolic compounds that are extensively distributed in plants with specific pharmacological properties, such as anti-inflammatory and anti-oxidant. Importantly, natural flavonoids have shown the protected function on the dextran sulfate sodium (DSS)-induced colitis in animals and lipopolysaccharides (LPS)-induced inflammatory response in macrophages. The purpose of this systematic review is to explore the efficacy of natural flavonoids in animal models of IBD (inflammatory bowel disease) and potential mechanisms in macrophages by meta-analysis and network pharmacology in preclinical studies. Relevant foundation studies were searched from January 2010 to November 2023 in databases like PubMed, Elsevier ScienceDirect, and Web of Science. Then, OriginPro software was used to extract values from images, and the analysis was performed using Review Manager 5.3. The retrieved data was analyzed according to the fixed-effects model and random-effects model. Subsequently, heterogeneity was evaluated using the I2 statistics. Lastly, network pharmacology was applied to confirm mechanisms of natural flavonoids on IBD. According to the results of meta-analysis, we found the natural flavonoids exhibited powerful therapeutic effects against IBD, which not only reversed colonic shortness (WMD = 1.33, 95% CI (1.07, 1.59), P < 0.00001), but also reduced histological score (SMD =  - 2.66, 95% CI (- 3.77, - 1.95), P < 0.00001) between natural flavonoid treatment groups compared with the experimental IBD model. Furthermore, treatment with natural flavonoids decreased the levels of tumor necrosis factor-α (TNF-α) in macrophages. Mechanistically, our summarized data substantiate that natural flavonoids alleviate LPS-induced M1 macrophage polarization, anti-oxidant, anti-inflammatory, maintain intestinal barrier, and inhibit the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in macrophages. Moreover, the results of network pharmacology also support this. This systematic review demonstrated the efficiency of natural flavonoids in treating IBD in preclinical research by meta-analysis and network pharmacology, which offered supporting evidence for clinical trial implementation. However, some limitations remain present, such as technique quality shortage, missed reports on account of negative results, failure to count sample size, and the risk of bias.

Ulcerative colitis (UC) represents a significant challenge to global health, underscoring the importance of developing novel alternative anti-colitis agents. Inhibition of the NLRP3 inflammasome in macrophages has emerged as a potential therapeutic strategy for UC. Pulchinenoside B4 (PB4) is a major component of traditional medicinal plants that demonstrated to possess promising anti-inflammatory properties. The aim of the present study was to assess whether PB4 alleviates dextran sodium sulfate (DSS)-induced colitis by inhibiting the NLRP3 inflammasome in macrophages and its potential molecular mechanism. We constructed DSS-induced colitis in C57BL/6 mice, and isolated mouse intestinal macrophages and epithelial cells to investigate the effect of PB4 on NLRP3 inflammasome, and confirmed our findings in DSS-induced NLRP3-/- mice. In addition, we constructed lipopolysaccharides (LPS)-induced macrophages in vitro and identified the target and molecular mechanism of PB4 through biolayer interference (BLI) and cell thermal migration (CETSA) in conjunction with dss induced macrophage-specific CD1d depletion (CD1d-/-) colitis. This study showed that PB4 had a strong anti-inflammatory effect on WT mice induced by DSS, but the protective effect on NLRP3-/- mice was no longer enhanced. Interestingly, PB4 inhibited the activation of NLRP3 inflammasome in colon macrophages without affecting intestinal epithelial cells. Mechanistically, PB4 may target CD1d, thereby reducing the AKT-STAT1-PRDX1-NF-κB signaling pathway and ultimately inhibiting the activation of the NLRP3 inflammasome. Macrophage-specific CD1d loss has been shown to reverse the protective effects of PB4. These findings have paved the way for the development of CD1d/NLRP3-based novel anti-colitis agents and will facilitate the future clinical translation of the plant-derived drug PB4.

Background/Objectives: A bidirectional association between inflammatory bowel disease (IBD) and periodontitis has been observed, yet their causal relationship remains unclear. This study aimed to investigate the potential causal links between these two inflammatory conditions through comprehensive genetic and molecular analyses. Methods: We conducted a bidirectional Mendelian randomization (MR) analysis integrated with bioinformatics approaches. The causal relationships were primarily evaluated using inverse variance weighting (IVW), complemented by multiple sensitivity analyses to assess the robustness of the findings. Additionally, we performed differential gene expression analysis using RNA sequencing data to identify co-expressed genes and shared inflammatory mediators between IBD and periodontitis, followed by pathway enrichment analysis. Results: Bidirectional MR analysis revealed significant causal associations between IBD and periodontitis (p-value < 0.05). Sensitivity analyses demonstrated the consistency of these findings, with no evidence of significant heterogeneity or horizontal pleiotropy (p-value > 0.05). Integrated bioinformatics analysis identified key immune regulators, particularly interleukin 1 beta (IL1B) and C-X-C motif chemokine receptor 4 (CXCR4), and inflammatory signaling pathways, including tumor necrosis factor (TNF-α) and interleukin 17 (IL17), as potential molecular mechanisms underlying the bidirectional relationship between these conditions. Conclusions: Our findings provide genetic evidence supporting a bidirectional causal relationship between IBD and periodontitis. Transcriptomic analysis revealed shared pathological mechanisms and identified crucial immune regulatory factors common to both diseases. These insights enhance our understanding of the molecular interplay between IBD and periodontitis, potentially informing new therapeutic strategies for both conditions.

Extracellular vesicles (EVs) derived from specific bacteria exert therapeutic potential on inflammatory diseases. Previous reports suggest the protective role of Odoribacter splanchnicus (O.splanchnicus) in inflammatory bowel disease (IBD). The effect of EVs derived from O.splanchnicus (Os-EVs) and the underlying mechanism on IBD were surveyed here.

Os-EVs were derived with ultracentrifugation before characterization by transmission electron microscopy and nanoparticle tracking analysis. Based on IBD model mice induced by dextran sulfate sodium (DSS), the effects of Os-EVs on IBD symptoms, intestinal barrier dysfunction, and colonic apoptosis, inflammation as well as NLRP3 inflammasome activation were analyzed. NLRP3 knockout mice were exploited to judge the role of NLRP3 in Os-EVs against IBD.

Os-EVs were typically shaped as a double concave disc (average diameter = 95 nm). The administration of Os-EVs attenuated DSS-induced body weight loss, colon shortening, disease activity index score, and histological injury in mice. Os-EVs could also relieve intestinal barrier dysfunction and colonic apoptosis, as evidenced by the up-regulation of zona occludens-1 and Occludin and the decrease of TUNEL-positive staining in colonic tissues of IBD mice. Os-EVs downregulated the expression of the interleukin-1β (IL-1β), tumor necrosis factor-α, and IL-6, and elevated IL-10, accompanied by blockage of the NLRP3 inflammasome activation in DSS-induced mice. Furthermore, NLRP3 knockout mice experiments revealed that the protective role of Os-EVs in IBD relies on regulating NLRP3.

Our finding indicated that Os-EVs effectively ameliorated IBD through repressing NLRP3, strongly supporting the potential of probiotic-derived EVs for alleviating IBD.

Dihydromyricetin (DHM), the primary active compound in vine tea possesses various pharmacological effects such as anti-inflammatory and antioxidant properties, along with high biosafety. However, its oral delivery remains a significant challenge. Montmorillonite (MMT), the primary component of bentonite, is a commonly used drug in the clinical treatment of gastrointestinal diseases and serves as an excellent drug carrier due to its intercalation capability. In this study, we intercalated DHM into the interlayer spaces of MMT via solution intercalation method combined with rotary evaporation and used it to treat ulcerative colitis in mice. SEM, XRD, and FTIR analyses confirmed the successful synthesis of the DHM/MMT intercalation compound. In vitro studies shown that DHM/MMT eliminated intracellular ROS and suppressed inflammatory genes IL-1β, IL-6, and TNF-α. Moreover, DHM/MMT demonstrated notable therapeutic effects in ulcerative colitis (UC) mice, significantly restoring the intestinal mucosa. Importantly, the therapeutic mechanism of DHM/MMT is closely linked to the inhibition of the NLRP3 signaling pathway. Additionally, this strategy modulated gut microbiota by increasing probiotics and suppressing harmful bacteria, thereby maintaining intestinal homeostasis. In conclusion, DHM/MMT presents a promising strategy for UC treatment.

Polyacylated anthocyanins are known for their enhanced stability and immunosuppressive properties. Although peonidin-3-O-(3,6-O-dimalonyl-β-D-glucoside) (P3GdM) from black corncobs has demonstrated notable antibacterial and stress-resistance effects in plants, its regulatory role in inflammatory bowel disease (IBD) remains unexplored. In this study, P3GdM was isolated from black corncobs, and its potential as a treatment for dextran sulfate sodium (DSS)-induced colitis in mice was evaluated. The findings revealed that P3GdM significantly mitigated clinical symptoms, reduced the disease activity index (DAI), suppressed the production of pro-inflammatory cytokines and endotoxins, and repaired the intestinal barrier. Furthermore, P3GdM markedly improved DSS-induced gut microbiota dysbiosis, significantly increasing microbial diversity and enhancing the relative abundance of critical bacterial species such as Akkermansia muciniphila and Lactobacillus reuteri, while also stimulating the production of short-chain fatty acids (SCFAs) and lactic acid. Correlation analyses further revealed strong associations between key microbial taxa, pro-inflammatory factors, clinical symptoms, tight junction proteins, and SCFAs. These findings provide support for the potential of P3GdM as an adjunct therapy for intestinal disorders, particularly colitis.

Despite evidence of the efficacy of decursinol angelate (DA), a prescription medication derived farom traditional Chinese medicine, in alleviating inflammatory bowel disease (IBD), the precise mechanisms behind its action remain unclear.

Lipopolysaccharides (LPS) and dextran sodium sulfate (DSS) induction were used as in vitro and in vivo models of IBD, respectively, to assess the role of DA in alleviating IBD. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the expression levels of pro-inflammatory cytokines in mouse serum, Western blot was performed to detect the expression of TXNIP/NLRP3 pathway tight junction (TJ) proteins in colon tissues and cells, and immunohistochemistry, immunofluorescence and immunohistochemistry, immunofluorescence and qRT-PCR were used to validate the proteins related to this signaling pathway. Molecular docking technique and co-immunoprecipitation (Co-IP) method assay were applied to evaluate the targeting effect of DA on NLRP3 proteins, and MCC950, a specific inhibitor of NLRP3, was used as a positive control for validation.

Our research indicates that DA's distinctive molecular mechanism could entail binding to the NLRP3 protein, thereby suppressing the activation of the NLRP3 pathway and diminishing the assembly and activation of the NLRP3 inflammasome, thus functioning as an anti-inflammatory agent.

DA may play a role in improving BD by inhibiting the activation of the ROS/TXNIP/NLRP3 signaling pathway and the release of inflammatory mediators, and by repairing the intestinal barrier function.

The role of gut microbiota in inflammatory disease development and progression has been recognized more recently. Inflammasome-mediated pyroptosis in involved in these diseases. This complex relationship between gut microbiota and inflammasome-mediated pyroptosis provides an important field of research. Bibliometric analysis provides a comprehensive understanding of this relationship, offering valuable insights into emerging research trends.

Leveraging data spanning from 2014 to 2023 sourced from the Web of Science Core Collection, our analysis was conducted using advanced tools such as SCImago Graphica, VOSviewer, and CiteSpace software. Visualizations were created using GraphPad Prism software. We explored the nuanced aspects of research hotspots, collaborative networks, and developing trends in this field.

A global bibliometric analysis identified 520 relevant studies spanning 41 countries and 887 institutions. Over the past decade, publication trends have shown consistent growth, with China and the United States leading the research output. Southern Medical University and Nanjing Medical University in China emerged as leading institutions in this filed. Prominent contributors include Jia Sun, Yuan Zhang, Wei Chen, Jing Wang, and Hongtao Liu from China, alongside Eicke Latz from Germany. High-impact journals such as Frontiers in Immunology and Nature Communications have been pivotal in disseminating research in this domain. Keyword analysis highlighted a primary focus on gut microbiota, NLRP3 inflammasome, pyroptosis pathways, and inflammatory diseases, themes that persist in recent studies. Furthermore, burst keyword analysis identified "butyrate" as the sole term currently experiencing a marked increase in research interest.

Research has been deeply focused on the gut microbiota and inflammasome triggered pyroptosis in years. Over the past decade, the exploration of how gut microbiota and NLRP3 or NLRP6 inflammasome-mediated pyroptosis has been an area of interest. Future investigations in this filed may primarily revolve around understanding the correlation between butyrate and NLRP3 inflammasome induced pyroptosis in relation to conditions. However, an in-depth analysis, through studies is crucial to uncover and elucidate the complex mechanisms linking these elements.

Rubia cordifolia L. has been formally included in the Chinese Pharmacopoeia and utilized for centuries as a traditional Chinese medicine. Mollugin, a quinone compound, is a major active compound extracted from Rubia cordifolia L. Mollugin was reported has multiple pharmacological activity, including anti-inflammatory, anti-tumor effects. However, the anti-inflammatory mechanism is not yet clear. In this study, we explored the anti-inflammatory activity and potential mechanism of mollugin in vitro and in vivo.

We explored the mechanisms that mollugin suppressed IL-1β expression through ZFP91 using various assays, including western blot, immunofluorescence, immunoprecipitation, MTT, RT-PCR, and ELISA assays in vitro. In vivo, oral administration of DSS induced colitis in mice and intraperitoneal injection of alum induced peritonitis in mice.

First, the results demonstrated that mollugin dramatically suppressed IL-1β secretion through reducing ZFP91 in macrophages. Crucially, we proved that mollugin inhibited K63-linked Pro-IL-1β ubiquitination through ZFP91 and limitated Pro-IL-1β cleavage efficacy. In addition, ZFP91-mediated Caspase-8 inflammasome component expression was inhibited by mollugin. Furthermore, mollugin inhibited the assembly of the Caspase-8 inflammasome complex by downregulating ZFP91. In vivo studies further revealed that mollugin improved DSS-induced colitis and alum-induced peritonitis in mice by reducing ZFP91. Notely, mollugin significantly altered the abundance of gut flora in DSS-induced colitis mice, which in turn ameliorated the colitis.

We present a novel finding that mollugin inhibition of ZFP91 is a crucial regulatory step, preventing undue inflammatory responses and thereby maintaining immune homeostasis. The current study offers new insight into the development of anti-inflammatory therapeutics targeting ZFP91.

Acanthoside B (Aca.B), a principal bioactive compound extracted from Pogostemon cablin, exhibits superior anti-inflammatory capacity. Ulcerative colitis is a nonspecific inflammatory bowel disease with unknown etiology. The potential of Aca.B as a therapeutic agent for ulcerative colitis is also unknown and remains an area for future investigation. In this study, we established both in vitro and in vivo models to investigate ulcerative colitis, utilizing Llipopolysaccharide (LPS)-stimulated MODE-K cells and dextran sulfate sodium (DSS)-induced colitis in mice, respectively. The progression of ulcerative colitis was evaluated through histologic analysis, body weight monitoring, and assessment of disease activity index assessment. Furthermore, the effects on pyroptosis were detected through immunoblot analysis. We found that Aca.B treatment significantly ameliorated LPS-induced injury in MODE-K cells, as evidenced by increased cell viability and inhibition of inflammatory response. Moreover, the Aca.B treatment attenuated pyroptosis-specific protein expression, caspase-1 activation, and inflammatory cytokine secretion. In the animal study, Aca.B administration improved bowel symptoms in DSS-induced colitis mice model. This was accompanied by reductionsreduced inweight, colon shortening, inflammatory cell infiltration, and cell pyroptosis in vivo. Furthermore, Aca.B diminished the accumulation of advanced glycation end-products (AGE), resulting in a decrease in the expression of the receptor of AGE (RAGE) and downstream phosphorylated P65 expression. e.The inhibition of the inflammatory response and pyroptosis by Aca.B depends on suppressing the AGE/RAGE pathway. This study confirms the effects of Aca.B on pyroptosis and ulcerative colitis, providing a fundamental evidence for translating Aca.B into clinical applications as an anti-inflammatory medicine.

The NOD-like receptor protein 3 (NLRP3) inflammasome is essential in innate immune-mediated inflammation, with its overactivation implicated in various autoinflammatory, metabolic, and neurodegenerative diseases. Pharmacological inhibition of NLRP3 offers a promising treatment strategy for inflammatory conditions, although no medications targeting the NLRP3 inflammasome are currently available. This study demonstrates that clioquinol (CQ), a clinical drug with chelating properties, effectively inhibits NLRP3 activation, resulting in reduced cytokine secretion and cell pyroptosis in both human and mouse macrophages, with a half maximal inhibitory concentration (IC50) of 0.478 μM. Additionally, CQ mitigates experimental acute peritonitis, gouty arthritis, sepsis, and colitis by lowering serum levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Mechanistically, CQ covalently binds to Arginine 335 (R335) in the NACHT domain, inhibiting NLRP3 inflammasome assembly and blocking the interaction between NLRP3 and its component protein. Collectively, this study identifies CQ as an effective natural NLRP3 inhibitor and a potential therapeutic agent for NLRP3-driven diseases.

Helminths can relieve the development of autoimmune diseases and inflammatory diseases, by inducing anti-inflammatory innate immune responses. Here, we report that CL7, a Cathepsin L protein secreted by Fasciola hepatica, inhibited the activation of the NF-κB and MAPK signaling resulting in reduced secretion of inflammatory mediators in macrophages. Furthermore，we found that CL7 could prevent dextran sulfate sodium (DSS) induced ulcerative colitis (UC). CL7 and ESP administration restored DSS-induced body weight loss, colon shortening, and injury, significantly decreased the disease activity index (DAI) and alleviated colonic epithelial injury. CL7 noticeably suppressed the DSS-triggered M1 polarization upregulation and inhibited IL-17 and other inflammatory mediator production in UC mice. Additionally, CL7 ameliorated DSS-induced microbiota dysbiosis. Results of Antibiotic treatment (ABX) and fecal microbial transplants (FMT) suggested that the gut microbiota played an important role in CL7 treating UC. These findings propose that CL7 could be a promising strategy for UC therapy.

Most spheroid models use size measurements as a primary readout parameter; some models extend analysis to T cell infiltration or perform caspase activation assays. However, to our knowledge, T cell motility analysis is not regularly included as an endpoint in imaging studies on cancer spheroids.

Here, we intend to demonstrate that motility analysis of macrophages and T cells is a valuable functional endpoint for studies on molecular interventions in the tumor microenvironment. In particular, T cell migration analysis represents the final step of effector function, as T cells engage with targets cells upon cytotoxic interaction, which is represented by an arrest within the spheroid volume. Therefore, T cell arrest is a novel readout parameter of T cell effector function in spheroids.

Here, we demonstrate that incubation of macrophages with nigericin for NLRP3 activation increases T cell velocity, but results in decreased T cellular arrest. This is paralleled by reduced rejection kinetics of pancreatic cancer spheroids in the presence of antigen-dependent T cells and nigericin-treated macrophages. Our model demonstrates consistent changes in T cell motility upon coculturing of T cells and tumors cells with macrophages, including influences of molecular interventions such as NLRP3 activation.

Motility analysis using a spheroid model of pancreatic cancer is a more sophisticated alternative to in vitro cytotoxicity assays measuring spheroid size. Ultimately, an optimized spheroid model might replace at least some aspects of animal experiments investigating T cell effector function.

Butyrate can strengthen the intestinal epithelial barrier. However, the mechanisms by which butyrate affects intestinal epithelial cells (IECs) pyroptosis in Crohn's disease (CD) remain unclear. In this study, we collected colonic biopsy samples from CD patients and healthy controls to assess pyroptosis levels. Our findings indicated elevated expression of pyroptosis markers in CD patients, alongside distinct morphological evidence of pyroptosis in IECs. We further investigated the effects of tributyrin on pyroptosis and the cGAS-STING pathway in a trinitrobenzene sulfonic acid-induced colitis rat model. Tributyrin significantly mitigated intestinal inflammation, reduced pathological progression, and inhibited pyroptosis and cGAS-STING pathway activation in the colitis rat model. Similarly, in an in vitro model of IECs pyroptosis, sodium butyrate inhibited pyroptosis and cGAS-STING pathway activation in HT-29 cells. Co-treatment with a cGAS-STING pathway activator and butyrate demonstrated that the activator reversed the inhibitory effects of butyrate on pyroptosis and cGAS-STING pathway activation in both the colitis rat model and HT-29 cells. Mechanistically, the cGAS-STING pathway was found to interact with NLRP3. Taken together, butyrate may mitigate intestinal inflammation in CD by suppressing cGAS-STING-NLRP3 axis-mediated IECs pyroptosis. These findings offer new insights into potential therapeutic strategies for managing CD.

Activation of the NLRP3 inflammasome and estrogen receptor α (ERα) has been shown to increase the risk of inflammatory bowel diseases (IBD) or promote disease recurrence. In previous work, we demonstrated that ERα regulated the transcription of NLRP3. However, the precise mechanism by which ERα modulates NLRP3 in IBD models remains unclear. In this study, we induced IBD in wild-type mice using DSS or TNBS, followed by treatment with the ERα-specific agonist PPT. The results showed that IBD symptoms and intestinal inflammation responses were significantly exacerbated after PPT treatment. Furthermore, the activation of ERα by PPT led to a marked increase in the expression of NLRP3 and pro-inflammatory cytokines, including IL-1β and IL-18, suggesting that ERα activation exacerbated intestinal inflammation and impaired mucosal healing during the recovery phase of inflammation. In contrast, ERα-knockout mice exhibited only mild symptoms when exposed to DSS or TNBS, with a concurrent reduction in NLRP3 expression, indicating that ERα plays a role in inflammation susceptibility. Similar findings were observed in NCM-460 cells, where the inflammation response was attenuated in ERα-knockdown cells. Importantly, we demonstrated that ERα interacted with the NLRP3 inflammasome and promoted its assembly. Collectively, we propose an underlying pathogenesis of IBD, that is, ERα can interact with the NLRP3 inflammasome and promote its expression and assembly, thereby exacerbating intestinal inflammation in IBD models. Therefore, ERα could serve as a potential therapeutic target for NLRP3 inflammasome-associated intestinal inflammation.

Besides various infectious and inflammatory complications, recent studies also indicated the significance of NLRP3 inflammasome in cancer progression and therapy. NLRP3-mediated immune response and pyroptosis could be helpful or harmful in the progression of cancer, and also depend on the nature of the tumor microenvironment. The activation of NLRP3 inflammasome could increase immune surveillance and the efficacy of immunotherapy. It can also lead to the removal of tumor cells by the recruitment of phagocytic macrophages, T-lymphocytes, and other immune cells to the tumor site. On the other hand, NLRP3 activation can also be harmful, as chronic inflammation driven by NLRP3 supports tumor progression by creating an environment that facilitates cancer cell proliferation, migration, invasion, and metastasis. The release of pro-inflammatory cytokines such as IL-1β and IL-18 can promote tumor growth and angiogenesis, while sustained inflammation may lead to immune suppression, hindering effective anti-tumor responses. In this review article, we discuss the role of NLRP3 inflammasome-mediated inflammatory response in the pathophysiology of various cancer types; understanding this role is essential for the development of innovative therapeutic strategies for cancer growth and spread.

NLRP3 inflammasome immoderate activation results in the occurrence of various inflammatory diseases, but the clinic medications targeting NLRP3 inflammasome are still not available currently. The strategy of drug repurposing can reorient the direction of therapy, which is an indispensable method of drug research. In this study, an antimicrobial agent chlorquinaldol (CQ) was conducted to assess the effect on NLRP3 inflammasome and novel clinical value on NLRP3-driven diseases.

The effect of CQ on NLRP3 inflammasome activation and pyroptosis was studied in mouse and human macrophages. ASC oligomerization, intracellular potassium, reactive oxygen species production, and NLRP3-ASC interaction were used to evaluate the suppression mechanism of CQ on inflammasome activation. Finally, the ameliorative effects of CQ in the model of LPS-induced peritonitis, dextran sodium sulfate (DSS)-induced colitis, and monosodium urate (MSU)-induced gouty arthritis were evaluated in vivo.

CQ is a highly powerful NLRP3 inhibitor that has feeble impact on the NLRC4 or AIM2 inflammasome activation in mouse and human macrophages. Further study indicated that CQ exhibits its suppression effect on NLRP3 inflammasome by blocking NLRP3-ASC interaction and hydroxyl on the benzene ring is vital for the assembly and activation of NLRP3 inflammasome. Furthermore, in vivo experiments demonstrated that administration of CQ has outstanding therapeutic action on LPS-induced peritonitis, DSS-induced colitis, and MSU-induced gouty inflammation in mice.

Collectively, the current study discoveries the antimicrobial agent CQ as a potentially specific NLRP3 inhibitor, and its use provides a feasible therapeutic approach for the treatment of NLRP3-driven diseases.

Silica-induced pulmonary fibrosis is an irreversible and progressive lung disease with limited treatments available. In this work, FDA-approved cannabidiol (CBD) was studied for its potential medical use in silicosis. In silicosis female C57BL/6 mice model, oral CBD or pirfenidone (PFD) on day 1 after intratracheal drip silica (150 mg/mL) and continued for 42 days. Lung inflammatory and fibrotic changes were studied using ELISA kits, H&E staining and Masson staining. Osteopontion (OPN) and α-smooth muscle actin (α-SMA) expression in lung tissues was determined using immunohistochemical staining. The results indicated that CBD attenuated silica-induced pulmonary inflammation and fibrosis. Human myeloid leukemia mononuclear cells (THP-1) were treated with silica (200 μg/mL) to induce cell damage, then CBD (10 μM, 20 μM) and PFD (100 μM) were incubated. In vitro experiments showed that CBD can effectively reduce the expression of NLRP3 inflammasome in THP-1 cells and subsequently block silica-stimulated transformation of fibromuscular-myofibroblast transition (FMT) by culturing human embryonic lung fibroblasts (MRC-5) in conditioned medium of THP-1 cells. Therefore, CBD exhibited the potential therapy for silicosis through inhibiting the silica-induced pulmonary inflammation and fibrosis via the NLRP3/TGF-β1/Smad2/3 signaling pathway.

NOD-like receptors (NLRs) are a family of cytosolic pattern recognition receptors (PRRs) implicated in the innate immune sensing of pathogens and damage signals. NLRs act as sensors in multi-protein complexes called inflammasomes. Inflammasome activity is necessary for the maintenance of intestinal homeostasis, although their aberrant activation contributes to the pathogenesis of several gastrointestinal diseases. In this review, we summarize the main features of the predominant types of inflammasomes involved in gastrointestinal immune responses and their implications in intestinal disease, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), celiac disease, and Colorectal Cancer (CRC). In addition, we report therapeutic discoveries that target the inflammasome pathway, highlighting promising novel therapeutic strategies in the treatment of intestinal diseases. Collectively, our understanding of the mechanisms of intestinal inflammasome activation and their interactions with other immune pathways appear to be not fully elucidated. Moreover, the clinical relevance of the efficacy of inflammasome inhibitors has not been evaluated. Despite these limitations, a greater understanding of the effectiveness, specificity, and reliability of pharmacological and natural inhibitors that target inflammasome components could be an opportunity to develop new therapeutic options for the treatment of intestinal disease.

Benzoylmesaconine (BMA), a major alkaloid derived from the traditional Chinese medicine Aconitum carmichaeli Debx, exhibits potent anti-inflammatory properties. However, the precise mechanism underlying its action remains unclear.

This study aimed to investigate the inhibitory mechanism of BMA on the NLRP3 inflammasome and assess its therapeutic efficacy in NLRP3-related metabolic diseases.

A classic NLRP3 inflammasome-activated bone marrow-derived macrophage (BMDM) model was established to evaluate BMA's effects on NLRP3 upstream and downstream protein expression, as well as pyroptosis. Two distinct animal disease models, MSU-induced gouty arthritis and DSS-induced colitis, were utilized to validate BMA's anti-inflammatory activity in vivo.

In vitro findings revealed that BMA can suppress NLRP3 inflammasome activation by inhibiting interleukin-1β (IL-1β) secretion and GSDMD-N protein expression. This mechanism involved blocking intracellular K+ efflux and interfering with the formation of NLRP3 inflammasomes. In vivo studies demonstrated that BMA significantly alleviated inflammatory symptoms in MSU-induced acute gout and DSS-induced colitis models.

These findings suggest that BMA effectively inhibits the activation of the NLRP3 signaling pathway through dual mechanisms: reducing intracellular K+ efflux and disrupting NLRP3 inflammasome assembly. This multifaceted action highlights the therapeutic potential of BMA for NLRP3-related diseases.

Cathelicidins have anti-inflammatory activity and chicken cathelicidin-2 (CATH-2) has shown to modulate immune response, but the underlying mechanism of its anti-inflammation is still unclear. Therefore, in this study, we investigated the anti-inflammatory activity of CATH-2 on murine peritoneal macrophages during avian pathogenic E. coli (APEC) infection. The results showed that CATH-2 priming significantly reduced the production of IL-1β, IL-6, IL-1α, and IL-12. In addition, CATH-2 significantly attenuated APEC-induced caspase-1 activation and the formation of an adaptor (ASC) of NLRP3 inflammasome, indicating that CATH-2 inhibits APEC-induced NLRP3 inflammasome activation. Furthermore, CATH-2 remarkably inhibited NF-κB and MAPK signaling pathways activation. Moreover, CATH-2 significantly inhibited mRNA expression of cathepsin B and inhibited lysosomal acidification, demonstrating that CATH-2 disrupts lysosomal function. In addition, promoting lysosomal acidification using ML-SA1 hampered the anti-inflammatory effect of CATH-2 on APEC-infected cells. In conclusion, our study reveals that CATH-2 inhibits APEC-induced inflammation via the NF-κB/NLRP3/MAPK pathway through the dysfunction of lysosome.