Yang Qi-Bin, Li Ling-Qin, Zhang Quan-Bo, He Yong-Long, Mi Qing-Sheng, Zhou Jing-Guo
Department of Rheumatology and Immunology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan Province, People's Republic of China.
Henry Ford Immunology Program, Departments of Dermatology and Internal Medicine, Henry Ford Health System, Detroit, MI, 48202, USA.
J Inflamm Res. 2021 May 11;14:1845-1858. doi: 10.2147/JIR.S307796. eCollection 2021.
MicroRNAs were identified as master-switch molecules limiting acute inflammatory response. This study investigated the potential role of microRNA (miR)-223 in the mechanism of gout.
Wild-type (WT) and miR-223 knock-out (KO) mice were used to evaluate the phenotypes of gout models. Inflammatory cytokines were measured in air pouch and peritoneal cavity lavage fluid. In addition to miR-223 level in gout patients, miR-223 and pro-inflammatory genes were examined in bone marrow-derived macrophages (BMDMs) from mice as well as peripheral blood mononuclear cells from healthy controls (HC) treated with monosodium urate (MSU) crystals in vitro.
MiR-223 was up-regulated in the early phase in BMDMs from WT mice after MSU challenge and decreased rapidly, and this was not observed in miR-223 KO mice in vitro. In addition, miR-223 was required for macrophages homeostasis. In comparison with WT mice in vivo, miR-223 deficiency exacerbated swelling index of MSU-induced inflammation in foot pad and ankle joint models. MiR-223 deficiency also markedly aggravated inflammatory cells infiltration and cytokines release including interleukin (IL)-1β, IL-6 and monocyte chemotactic protein-1 (MCP-1) in the air pouch and peritonitis models. In the in vitro experiments, miR-223 deficiency promoted the inflammatory response by targeting NLR family pyrin domain containing protein 3 (NLRP3). Besides, miR-223 level was down-regulated in gout patients and in HC exposed to MSU in vitro.
MiR-223 was down-regulated in gout patients and miR-223 deficiency exacerbated inflammatory response in diverse murine models, suggesting that up-regulation of miR-223 could be a potential therapeutic strategy for alleviating gouty inflammation.
微小RNA被确定为限制急性炎症反应的主开关分子。本研究调查了微小RNA（miR）-223在痛风发病机制中的潜在作用。
使用野生型（WT）和miR-223基因敲除（KO）小鼠评估痛风模型的表型。在气袋和腹腔灌洗液中检测炎性细胞因子。除了检测痛风患者的miR-223水平外，还检测了来自小鼠的骨髓源性巨噬细胞（BMDM）以及体外接受尿酸钠（MSU）晶体处理的健康对照（HC）外周血单核细胞中的miR-223和促炎基因。
在MSU刺激后，WT小鼠BMDM中的miR-223在早期上调并迅速下降，而在体外miR-223 KO小鼠中未观察到这种情况。此外，巨噬细胞稳态需要miR-223。与体内WT小鼠相比，miR-223缺乏加剧了MSU诱导的足垫和踝关节模型炎症的肿胀指数。miR-223缺乏还显著加重了气袋和腹膜炎模型中的炎性细胞浸润和细胞因子释放，包括白细胞介素（IL）-1β、IL-6和单核细胞趋化蛋白-1（MCP-1）。在体外实验中，miR-223缺乏通过靶向含NLR家族pyrin结构域蛋白3（NLRP3）促进炎症反应。此外，痛风患者和体外暴露于MSU的HC中的miR-223水平下调。
痛风患者中miR-223下调，miR-223缺乏在多种小鼠模型中加剧炎症反应，提示上调miR-223可能是减轻痛风性炎症的潜在治疗策略。
