Phillyrin inhibits oxidative stress and neutrophil extracellular trap formation through the KEAP1/NRF2 pathway in gouty arthritis.

IF 3.3 4区 医学 Q3 IMMUNOLOGY
Immunologic Research Pub Date : 2024-12-01 Epub Date: 2024-10-22 DOI:10.1007/s12026-024-09548-8
Xiangfeng Xu, Yao Lu, Rong Shen, Li Fang
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引用次数: 0

Abstract

Gouty arthritis (GA) is an inflammatory disorder characterized by deposition of monosodium urate (MSU) crystal in joints. Phillyrin, a natural compound with anti-inflammatory properties, shows promise in mitigating inflammatory responses. This study investigates the therapeutic potential of phillyrin in GA and explores its mechanisms of action. GA was induced in mice via intraarticular MSU injection, and joint inflammation, inflammatory cell infiltration, and their level in serum/tissue were assessed. Key proteins in the NF-κB and NLRP3 pathways were examined using western blot analysis. The impact of phillyrin on oxidative stress, neutrophil extracellular trap (NET) formation, and neutrophil accumulation was evaluated by measuring CD11b + Ly6G + cells, MPO, CitH3, extracellular DNA ratio, and oxidative stress markers. In vitro studies assessed the effects of phillyrin on oxidative stress, cell viability, cytokine production, and NET formation in MSU-treated neutrophils. The KEAP1/NRF2 pathway's role was analyzed using ML385, an NRF2 inhibitor. Phillyrin significantly reversed MSU-induced ankle swelling and inflammatory cell infiltration in joint tissues. It suppressed pro-inflammatory cytokines and proteins in the NF-κB and NLRP3 pathways. Phillyrin reduced neutrophil infiltration, evidenced by lower MPO activity and NET formation, marked by reduced CitH3 expression. In vitro, phillyrin inhibited inflammatory marker expression and NET formation without affecting cell viability. It also restored antioxidant enzyme levels and reduced ROS production, regulating the KEAP1/NRF2 pathway, enhancing NRF2 expression and stability. These effects were reversed by NRF2 inhibition with ML385. Phillyrin alleviates GA by reducing joint inflammation, inhibiting NET formation, and suppressing oxidative stress through NRF2 modulation.

Phillyrin通过KEAP1/NRF2途径抑制痛风性关节炎的氧化应激和中性粒细胞胞外陷阱的形成。
痛风性关节炎(GA)是一种以单钠尿酸盐(MSU)晶体在关节中沉积为特征的炎症性疾病。菲利林是一种具有抗炎特性的天然化合物,有望减轻炎症反应。本研究调查了菲利林对 GA 的治疗潜力,并探讨了其作用机制。通过关节内注射 MSU 诱导小鼠出现 GA,并评估关节炎症、炎症细胞浸润及其在血清/组织中的水平。使用 Western 印迹分析法检测了 NF-κB 和 NLRP3 通路中的关键蛋白。通过测量 CD11b + Ly6G + 细胞、MPO、CitH3、细胞外 DNA 比率和氧化应激标记物,评估了菲力蛋白对氧化应激、中性粒细胞胞外捕获物(NET)形成和中性粒细胞聚集的影响。体外研究评估了菲利灵对氧化应激、细胞活力、细胞因子产生和 MSU 处理的中性粒细胞中 NET 形成的影响。使用 NRF2 抑制剂 ML385 分析了 KEAP1/NRF2 通路的作用。菲利林能明显逆转 MSU 引起的踝关节肿胀和关节组织中的炎性细胞浸润。它抑制了促炎细胞因子以及 NF-κB 和 NLRP3 通路中的蛋白质。菲力蛋白可减少中性粒细胞的浸润,表现为 MPO 活性降低和 NET 的形成,表现为 CitH3 表达减少。在体外,菲利林抑制了炎症标志物的表达和NET的形成,而不影响细胞的活力。它还能恢复抗氧化酶的水平,减少 ROS 的产生,调节 KEAP1/NRF2 通路,增强 NRF2 的表达和稳定性。用 ML385 抑制 NRF2 可逆转这些影响。通过调节 NRF2,Phillyrin 可减轻关节炎症、抑制 NET 的形成和抑制氧化应激,从而缓解 GA。
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来源期刊
Immunologic Research
Immunologic Research 医学-免疫学
CiteScore
6.90
自引率
0.00%
发文量
83
审稿时长
6-12 weeks
期刊介绍: IMMUNOLOGIC RESEARCH represents a unique medium for the presentation, interpretation, and clarification of complex scientific data. Information is presented in the form of interpretive synthesis reviews, original research articles, symposia, editorials, and theoretical essays. The scope of coverage extends to cellular immunology, immunogenetics, molecular and structural immunology, immunoregulation and autoimmunity, immunopathology, tumor immunology, host defense and microbial immunity, including viral immunology, immunohematology, mucosal immunity, complement, transplantation immunology, clinical immunology, neuroimmunology, immunoendocrinology, immunotoxicology, translational immunology, and history of immunology.
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