NLRP3 inflammasome inhibitor cucurbitacin B suppresses gout arthritis in mice

in Journal of Molecular Endocrinology
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  • 1 Department of Endocrinology, Tongji, Hospital, School of Medicine, Tongji University, Shanghai, China

Correspondence should be addressed to L Li: dalingll@126.com

Gouty arthritis is a common inflammatory disease characterized by monosodium urate (MSU) crystal-induced nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome activation with upregulated caspase 1 protease and IL-1β in macrophages. Cucurbitacin B (CuB) is a tetracyclic triterpene that possesses a potential anti-inflammatory activity. However, the immunomodulatory and anti-inflammatory effects of CuB on gout have not been well characterized. Therefore, the purpose of the present study was to determine whether CuB exhibits anti-inflammatory effects on gout and to analyze the underlying molecular mechanism. We examined the effects of CuB on various stimuli-activated bone marrow-derived macrophages (BMDMs) and in a mouse model with MSU-induced acute gouty arthritis. Our results demonstrated that CuB effectively suppressed multiple stimuli-activated IL-1β secretion by interrupting NLRP3 inflammasome complex formation, inhibiting NLRP3 inflammasome activation and suppressing key enzymes of glycolysis in macrophages. Consistent with this, CuB pretreatment also ameliorated MSU-induced arthritis in vivo models of gout arthritis, manifested by reduced foot swelling and inflammatory cell infiltration. Taken together, our data provide the evidence that CuB is an NLRP3 inflammasome inhibitor with therapeutic potential for treating NLRP3 inflammasome-mediated diseases, especially gouty arthritis.

Supplementary Materials

    • Supplementary Table 1 Gene-specific primers for RT-qPCR analysis.
    • Supplementary Fig.1 CuB shows no effect on cell viability of activated BMDMs The cell viability of BMDMs treated with different concentrations of CuB (0.01, 0.1, 1 μmol/L) in the presence of LPS plus ATP (A) or LPS plus MSU (B) was measured by CCK-8 assay. Data are expressed as mean ± SD, n = 5.
    • Supplementary Fig.2 CuB reduces the production of TNF-α and IL-18 BMDMs pretreated with different concentrations of CuB (0.01, 0.1, 1 μmol/L) for 12 h, followed by LPS for 4 h and ATP for 1 h, mRNA levels of Tnf-α (A) and Il-18 (B) were measured by RT-qPCR. Data are expressed as mean ± SD, n = 4, *P < 0.05; **P < 0.01.

 

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