A preliminary study on NLRP3 activation and the interventional effects of MCC950 in Con A-induced EAH mice

Introduction

The first-line treatment for autoimmune hepatitis (AIH) consists of glucocorticoids in combination with azathioprine. Second-line and rescue regimens involve glucocorticoids paired with other immunosuppressants such as mycophenolate mofetil or calcineurin inhibitors (e.g., cyclosporine A, tacrolimus), as well as biologics including rituximab and infliximab (1). However, these therapies still face challenges related to inadequate disease control, relapse, and significant adverse effects. Moreover, the high cost of certain immunosuppressants and biologics imposes a considerable long-term financial burden on patients and their families (2). Given these limitations, the development of novel therapeutic agents holds substantial scientific and clinical relevance. To advance the understanding of AIH pathogenesis and to facilitate the discovery and evaluation of new treatments, various animal models have been established to replicate the immune microenvironment of AIH (3). Among these, the Con A-induced experimental autoimmune hepatitis (EAH) mouse model—a T lymphocyte-mediated acute liver injury model—is widely recognized for its ability to effectively mimic AIH. Its histological features, such as lymphocytic infiltration and interface hepatitis, along with serological markers like elevated transaminase levels, closely resemble those observed in patients with AIH (4).

The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex composed of NLRP3, ASC, and pro-caspase-1, and plays a key role in the innate immune system by recognizing pathogens and danger signals (5). Upon activation, the NLRP3 inflammasome promotes the expression of chemokines and induces pyroptosis, contributing significantly to inflammatory liver injury and fibrosis (6). Recent studies indicate that the NLRP3 inflammasome plays a crucial role not only in the pathogenesis of various liver diseases—including alcoholic hepatitis, acetaminophen-induced liver injury, biliary atresia, and metabolic dysfunction-associated fatty liver disease (MAFLD) (7-10)—but also in Con A-induced hepatitis (11). In a Con A-induced EAH mouse model, Luan et al. observed elevated levels of NLRP3, caspase-1, and interleukin (IL)-1β, along with hepatic pyroptosis. Subsequent in vivo intervention with recombinant human IL-1 receptor antagonist significantly reduced NLRP3 inflammasome activation in these mice (12). Mohamed et al. demonstrated that cucurbitacin E glucoside can protect against Con A-induced liver injury by inhibiting mRNA expression of NLRP3 and related genes, thereby blocking NF-κB/NLRP3 signaling (13). Therefore, targeting the NLRP3 inflammasome pathway may represent a promising therapeutic strategy for hepatitis, including AIH.

MCC950 is a potent and selective inhibitor of the NLRP3 inflammasome, demonstrating high specificity in suppressing NLRP3 activity, which subsequently reduces the production of caspase-1 and the pro-inflammatory cytokines IL-1β and IL-18. Notably, MCC950 does not inhibit the activation of other inflammasomes such as AIM2, NLRC4, or NLRP1 (14), underscoring its high selectivity for NLRP3. The therapeutic potential of MCC950 in NLRP3-driven inflammatory and autoimmune diseases has been extensively studied in conditions including systemic lupus erythematosus, rheumatoid arthritis, and cryopyrin-associated periodic syndromes (15,16). For instance, Mridha et al. reported that MCC950 ameliorates hepatic inflammation and fibrosis in a non-alcoholic steatohepatitis mouse model, likely through blocking cholesterol crystal-mediated NLRP3 inflammasome activation in myeloid cells (17). Similarly, Qu et al. demonstrated that MCC950 alleviates cholestatic liver injury by inhibiting NLRP3 inflammasome activation and reducing the release of inflammatory cytokines (18).

Based on the established Con A-induced EAH mouse model, this study aims to analyze the expression levels of NLRP3 inflammasome pathway-related molecules and the extent of pyroptosis in the liver tissues of EAH mice. Using MCC950—a highly selective and potent NLRP3 inhibitor—as an interventional agent, we will preliminarily investigate the therapeutic effects and underlying mechanisms of MCC950 pretreatment in EAH mice. We present this article in accordance with the ARRIVE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0013/rc).

Methods

Materials

Con A was purchased from Sigma-Aldrich (St. Louis, USA). MCC950 was obtained from MedChemExpress (Monmouth Junction, USA). The FAM-FLICA Caspase-1 Assay kit was sourced from ImmunoChemistry Technologies (Davis, USA). ELISA kits were supplied by Wuhan Huamei Biological Co., Ltd. (Wuhan, China). qPCR kits were acquired from ThermoFisher Scientific (Waltham, USA). Antibodies against IL-1β and IL-18 were purchased from Affinity Biosciences Pty Ltd. (Melbourne, Australia). Antibodies targeting NLRP3, caspase-1, and β-actin were procured from Wuhan San Ying Biotechnology Co., Ltd. (Wuhan, China).

Animal models

Six-week-old male C57BL/6 mice weighing approximately 20 g were purchased from Wuhan Shulaibao Biological Technology Co., Ltd. (Wuhan, China). After one week of acclimatization, the mice were used to establish a Con A-induced EAH model (19). EAH was induced by tail vein injection of Con A at a dose of 15 mg/kg. Serum and liver tissue samples were collected at 0, 6, 12, and 24 h post‑injection. Blood samples were centrifuged at 1,000 g for 15 min at 4 ℃ to obtain serum. To evaluate the intervention effect, an additional MCC950 group was included. In this group, MCC950 (50 mg/kg, 5 mg/mL) was administered via intraperitoneal injection 30 min before Con A injection, and mice were euthanized at 12 h after Con A administration for sample collection. Six mice were used per time point per experimental group. As no mortality occurred, a simple random sampling method was employed to select mice (n=3 for specific analyses) from the available pool, ensuring each mouse had an equal probability of being selected. Experiments were performed under a project license (No. [2024] 4115) granted by the Animal Ethics Committee of Huazhong University of Science and Technology, in compliance with national and institutional guidelines for the care and use of animals. A protocol was prepared before the study without registration.

Liver histology

Liver tissues previously fixed in 4% paraformaldehyde were dehydrated, embedded in paraffin, and sectioned for HE staining. Histological liver injury was assessed according to the Ishak scoring system (20). Additionally, paraffin-embedded liver sections were subjected to immunohistochemical staining, and the results were evaluated under a microscope.

Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), IL-1β, IL-18

Serum levels of ALT, AST, IL-1β, and IL-18 were measured using ELISA kits (Wuhan Huamei Biological Co., Ltd., Wuhan, China).

Western blot

Liver tissue blocks were homogenized in RIPA lysis buffer and centrifuged to obtain the supernatant. Protein concentration was determined using a BCA protein assay kit (Beyotime, Shanghai, China). Gels were prepared with an SDS-PAGE gel preparation kit (Boster Biological Technology, Wuhan, China). Equal amounts of total protein (20 µg) were separated by SDS-PAGE and transferred onto PVDF membranes. The membranes were blocked with 3% BSA at room temperature for 2 hours, followed by overnight incubation with primary antibodies (against NLRP3, caspase-1, IL-1β, and IL-18) at 4 ℃. Subsequently, the membranes were incubated with secondary antibodies at room temperature for 2 hours. Protein bands were visualized using an ECL detection system, and band intensities were quantified with ImageJ software.

qPCR

Liver tissue was homogenized in lysis buffer and ground into a uniform homogenate. After multiple rounds of centrifugation and washing, the precipitate was transferred to a new RNase-free EP tube. RNA was then dissolved in RNA dissolution buffer, and residual DNA in the RNA template was removed. The resulting cDNA was subjected to qPCR. Data were analyzed based on the Ct values obtained from qPCR, and relative gene expression levels were calculated using the 2^-ΔΔct method.

Pyroptosis

The level of pyroptosis was assessed using the FAM-FLICA Caspase-1 Assay (ImmunoChemistry Technologies, USA). Fresh liver tissue was frozen, sectioned, and incubated with the FLICA working solution at 37 ℃ for 1 h in the dark, allowing FLICA reagent to bind to activated caspase-1. Subsequently, sections were counterstained with Hoechst 33342 and propidium iodide (PI). Fluorescence microscopy was used to visualize the green fluorescence signal (FLICA-labeled caspase-1), blue fluorescence (Hoechst 33342-stained nuclei), and red fluorescence (PI-stained necrotic cells).

Statistical analysis

Statistical analysis was performed using SPSS software (version 26.0). The normality of continuous variables was assessed with the Kolmogorov-Smirnov (K-S) test. Normally distributed data are expressed as mean ± standard deviation (SD). Differences among multiple groups were examined by one‑way analysis of variance (ANOVA), followed by pairwise multiple comparisons using Tukey’s HSD post‑hoc test. P<0.05 was considered statistically significant (*P<0.05, **P<0.01, ***P<0.001).

Results

Expression of NLRP3 inflammasome pathway in the liver tissue of Con A-induced EAH mice

Serum levels of ALT, AST, IL-1β, and IL-18 in EAH mice showed a significant increase at 6 h, peaked at 12 h, and subsequently declined by 24 h (Figure 1A). Histopathological examination revealed occasional spotty necrosis of hepatocytes at 6 h post-injection. By 12 h, focal necrosis was observed in most hepatic lobules and around portal areas, with local bridging necrosis also evident. At 24 h, the extent of liver necrosis further intensified, with prominent bridging necrosis between portal tracts and central veins, accompanied by hepatocyte nuclear pyknosis or lysis (Figure 1B).

Figure 1 Assessment of liver injury, NLRP3 inflammasome pathway-related molecular expression, and pyroptosis in the liver tissue of EAH mice. (A) Serum levels of ALT, AST, IL-1β, and IL-18 in EAH mice. (B) Representative H&E-stained liver tissue sections (200× magnification). (C) Protein expression of NLRP3, caspase-1, IL-1β, and IL-18 analyzed by western blot. (D) mRNA expression levels of NLRP3, caspase-1, IL-1β, and IL-18. (E) Immunohistochemical staining of NLRP3, caspase-1, IL-1β, and IL-18 in liver tissue (the black arrows indicate positive results). (F) Detection of pyroptosis using the FAM-FLICA Caspase-1 assay (200× magnification). Cells were stained with FAM-YVAD-FMK (green), PI (red), and Hoechst 33342 (blue) for nuclei. P<0.05 was considered statistically significant (*, P<0.05; **, P<0.01; ***, P<0.001). ALT, alanine aminotransferase; AST, aspartate aminotransferase; EAH, experimental autoimmune hepatitis; H&E, hematoxylin and eosin; IL, interleukin; NLRP3, NOD-like receptor family pyrin domain containing 3; PI, propidium iodide.

Western blot analysis indicated that the protein expression of NLRP3, caspase-1, IL-1β, and IL-18 increased as early as 6 h after Con A injection, peaked at 12 h, and decreased by 24 h (Figure 1C). Similarly, their mRNA levels began to rise at 6 h, reached a peak at 12 h, and declined at 24 h (Figure 1D). Immunohistochemical staining at 12 h post-injection demonstrated markedly elevated expression of NLRP3, caspase-1, IL-1β, and IL-18, predominantly localized around portal areas or within necrotic regions (indicated by black arrows, Figure 1E). Moreover, pyroptosis levels were significantly increased at 6, 12, and 24 h after Con A administration (Figure 1F).

MCC950 alleviates liver pathological injury, suppresses the NLRP3 inflammasome pathway, and reduces pyroptosis in EAH mice

Serum levels of ALT, AST, IL-1β, and IL-18 were significantly lower in the Con A + MCC950 group compared to the Con A group (Figure 2A). Histopathological analysis showed that liver lobule boundaries in the Con A + MCC950 group remained discernible, with only occasional hepatocyte necrosis (indicated by black arrows), characterized by nuclear fragmentation or lysis. The overall degree of liver injury was markedly milder than that in the Con A group, indicating that MCC950 alleviates pathological liver damage in EAH mice (Figure 2B).

Figure 2 Assessment of liver injury, NLRP3 inflammasome pathway-related molecular expression, and pyroptosis in the liver tissue of EAH mice following MCC950 pretreatment. (A) Serum levels of ALT, AST, IL-1β, and IL-18 in EAH mice. (B) Representative H&E-stained liver tissue sections (200× magnification, and the black arrows indicate necrotic areas). (C) Protein expression of NLRP3, caspase-1, IL-1β, and IL-18 analyzed by western blot. (D) mRNA expression levels of NLRP3, caspase-1, IL-1β, and IL-18. (E) Immunohistochemical staining of NLRP3, caspase-1, IL-1β, and IL-18 in liver tissue (the black arrows indicate positive results). (F) Detection of pyroptosis using the FAMFLICA Caspase-1 assay (200× magnification). Cells were stained with FAM-YVAD-FMK (green), PI (red), and Hoechst 33342 (blue) for nuclei. P<0.05 was considered statistically significant (ns, no significance; *, P<0.05; ***P<0.001). ALT, alanine aminotransferase; AST, aspartate aminotransferase; EAH, experimental autoimmune hepatitis; H&E, hematoxylin and eosin; IL, interleukin; NLRP3, NOD-like receptor family pyrin domain containing 3; PI, propidium iodide.

Western blot analysis revealed that the protein expression of NLRP3, caspase-1, IL-1β, and IL-18 was significantly lower in the Con A + MCC950 group than in the Con A group (Figure 2C). Immunohistochemical staining further confirmed a notable reduction in the expression of these proteins in the Con A + MCC950 group (Figure 2D). Correspondingly, their mRNA levels were also significantly decreased in the Con A + MCC950 group compared to the Con A group (Figure 2E). In addition, the level of pyroptosis was substantially reduced in the Con A + MCC950 group relative to the Con A model group (Figure 2F).

Discussion

In this study, we successfully established a Con A-induced EAH mouse model. Six hours after Con A injection, serum levels of ALT and AST began to rise, accompanied by initial liver injury characterized by sporadic spotty necrosis of hepatocytes. At 12 hours post-injection, both ALT and AST levels peaked, and significant pathological damage was observed in the liver, manifesting as multiple patchy necrotic areas with inflammatory cell infiltration. By 24 hours, although serum transaminase levels declined, hepatic injury continued to progress, with further expansion of necrotic regions. These findings are consistent with previous reports. Hao et al. demonstrated that serum transaminase levels peaked at 12 hours after Con A injection, and hepatic lobular structure was disrupted with increased necrotic areas at 24 hours (21). Moreover, it has been shown that a single dose of Con A can rapidly induce immune-mediated liver injury within 6–24 hours, with the most severe damage occurring between 8–12 hours. This injury is characterized by elevated plasma ALT and AST levels, marked histopathological changes, and substantial inflammatory cell infiltration (22,23).

Overactivation of the NLRP3 inflammasome triggers inflammation, thereby promoting disease progression and impairing tissue and organ function (24). Consistent with the findings of Luan et al., who demonstrated a key role for the NLRP3 inflammasome in Con A-induced hepatitis (12), our study also observed activation of the NLRP3 inflammasome in the liver tissue of EAH mice. Starting from 6 hours post‑injection, expression of NLRP3 inflammasome pathway-related molecules progressively increased, peaking at 12 hours, along with a marked rise in pyroptosis levels. This indicates that NLRP3 inflammasome activation occurs in EAH mice and contributes to inflammatory liver injury, playing an important role in the pathogenesis. Activation of the NLRP3 inflammasome requires a two-signal process. The first signal, often derived from pathogen-associated molecular patterns or cytokines, upregulates the expression of NLRP3, pro-IL-1β, and pro-IL-18. The second signal, mainly mediated by damage-associated molecular patterns, induces NLRP3 oligomerization, recruits ASC and pro-caspase-1, and promotes assembly of the NLRP3 inflammasome, leading to caspase-1 activation (5,17). Once activated, NLRP3 cleaves pro-caspase-1 into active caspase-1, which then processes pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18. IL-1β stimulates the expression of other pro-inflammatory mediators and recruits neutrophils into the liver, exacerbating the inflammatory response (13). Subsequently, gasdermin D (GSDMD) induces pyroptosis via its N-terminal fragment and regulates IL-1β secretion (25). Our results showed that by 24 hours after Con A injection, the expression of NLRP3 inflammasome pathway molecules and the level of pyroptosis began to decline. This may reflect a self‑regulatory response in EAH mice, wherein antiinflammatory mechanisms are upregulated to counteract excessive pro-inflammatory signaling and limit further liver injury, followed by a reduction in pyroptosis (23). Furthermore, the expression trends of NLRP3, caspase-1, IL-1β, and IL-18 paralleled the changes in serum transaminase levels, reinforcing the correlation between NLRP3 inflammasome pathway activation and Con A-induced hepatitis. Previous studies have shown that transaminase and cytokine levels in EAH mice start to decline 24 hours after Con A injection and return to near-normal levels around 72 hours (19,21).

MCC950, as a potent inhibitor of the NLRP3 inflammasome, exhibits broad pharmacological activity. This study is the first to explore the protective effect of MCC950 against Con A-induced EAH, aiming to evaluate its potential therapeutic value for AIH. Our findings demonstrate that pretreatment with MCC950 significantly reduces serum transaminase levels, markedly decreases hepatocyte necrosis, and improves histopathological liver injury in EAH mice. These results indicate that MCC950 exerts a robust hepatoprotective effect in this model, providing compelling experimental evidence for its potential application in the treatment of AIH.

Research has shown that MCC950 exerts notable protective effects in various liver disease models and may also possess antifibrotic potential. For instance, MCC950 has demonstrated anti-inflammatory activity in models of alcohol-induced liver injury, non-alcoholic steatohepatitis, cholestasis, and acetaminophen-induced hepatotoxicity (14). Furthermore, MCC950 has been found to effectively suppress steatosisassociated liver injury in high-fat diet-fed mice without causing adverse effects (26). Yan et al. reported that MCC950 alleviates carbon tetrachloride-induced acute liver injury by enhancing the functions of M2 macrophages and myeloid-derived suppressor cells, which leads to reduced levels of IL-1β, IL-2, IL-6, and TNF-α, along with increased production of IL-10 (27). Thioacetamide, a hepatotoxin used to model liver fibrosis, was recently shown to induce liver injury that can be significantly ameliorated by MCC950 treatment, as evidenced by improvements in biochemical, histological, and immunological markers. These findings indicate that MCC950 mitigates oxidative stress and inflammation in thioacetamideinduced liver injury, further supporting its potent hepatoprotective properties (28).

This study demonstrates that MCC950 effectively inhibits the activation of the NLRP3 inflammasome in the liver tissue of Con A-induced EAH mice. MCC950 significantly reduced the expression levels of NLRP3, caspase-1, IL-1β, and IL-18, as well as the extent of pyroptosis, in the liver tissue of EAH mice. These results not only reaffirm the previously reported antiinflammatory properties of MCC950 but also elucidate its mechanism of action, specifically through the suppression of the NLRP3 inflammasome. Existing studies indicate that MCC950 may inhibit ASC oligomerization by interfering with intracellular chloride efflux (14). The NACHT domain, which serves as the central functional region of NLRP3, mediates its selfoligomerization and is essential for NLRP3 inflammasome activation (29). Furthermore, Coll et al. found that MCC950 directly interacts with the Walker B motif within the NACHT domain of NLRP3, thereby inhibiting NLRP3 activation and inflammasome assembly (30).

To date, there have been no reports on the protective effect of MCC950 against Con A-induced EAH liver injury. However, studies in other liver injury models have documented its efficacy. For example, Mridha et al. showed that MCC950 suppresses NLRP3 activation by blocking cholesterol crystal formation in myeloid cells in an obese diabetic mouse model (17). Similarly, Wang et al. demonstrated that MCC950 inhibits the expression of NLRP3 and IL-1β in a methionine-choline deficient diet-induced MAFLD model (31). In cholestatic liver injury models, MCC950 significantly suppresses NLRP3 activation and reduces the production of pro-inflammatory cytokines IL-1β and IL-18 (18). Additionally, in aged mouse models, MCC950 alleviates alcohol-induced liver fibrosis by inhibiting the NLRP3 inflammasome, thereby attenuating inflammation and decreasing hepatocyte-derived danger signals (32). In summary, MCC950 mitigates liver injury—including EAH—through inhibition of the NLRP3 inflammasome pathway. These findings provide experimental support for MCC950 as a potential therapeutic agent for AIH. A key limitation of this study is that the role of the NLRP3 inflammasome in AIH was only confirmed in an animal model. Furthermore, as MCC950 was administered only as a preventative measure, the therapeutic mechanisms of inhibiting NLRP3 require further investigation.

Conclusions

In this study, a Con A-induced EAH mouse model was successfully established. The NLRP3 inflammasome was activated in EAH mice, as evidenced by significantly elevated expression of NLRP3, caspase-1, IL-1β, and IL-18, along with increased pyroptosis. MCC950 alleviated liver injury in EAH mice by inhibiting NLRP3 inflammasome activation. Specifically, pretreatment with MCC950 led to a marked reduction in serum transaminase levels, substantial improvement in liver histopathology, and significant decreases in the expression of NLRP3, caspase-1, IL-1β, and IL-18, as well as in pyroptosis.

Acknowledgments

We thank all the subjects who participated in our study.

Footnote

Reporting Checklist: The authors have completed the ARRIVE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0013/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0013/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0013/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-1-0013/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Experiments were performed under a project license (No. [2024] 4115) granted by the Animal Ethics Committee of Huazhong University of Science and Technology, in compliance with national and institutional guidelines for the care and use of animals.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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