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Molecular basis of carrageenan-induced cytokines production in macrophages.
Cell Communication and Signaling ( IF 8.2 ) Pub Date : 2020-09-07 , DOI: 10.1186/s12964-020-00621-x
Alexandre H Lopes 1 , Rangel L Silva 1 , Miriam D Fonseca 1 , Francisco I Gomes 1 , Alexandre G Maganin 1 , Lucas S Ribeiro 2 , Lucas Maciel Mauriz Marques 3 , Fernando Q Cunha 1 , Jose C Alves-Filho 1 , Dario S Zamboni 4 , Norberto P Lopes 3 , Bernardo S Franklin 2 , Aurélie Gombault 5 , Fernando Silva Ramalho 6 , Valerie F J Quesniaux 5 , Isabelle Couillin 5 , Bernhard Ryffel 5 , Thiago M Cunha 1
Affiliation  

Low molecular weight carrageenan (Cg) is a seaweed-derived sulfated polysaccharide widely used as inflammatory stimulus in preclinical studies. However, the molecular mechanisms of Cg-induced inflammation are not fully elucidated. The present study aimed to investigate the molecular basis involved in Cg-induced macrophages activation and cytokines production. Primary culture of mouse peritoneal macrophages were stimulated with Kappa Cg. The supernatant and cell lysate were used for ELISA, western blotting, immunofluorescence. Cg-induced mouse colitis was also developed. Here we show that Cg activates peritoneal macrophages to produce pro-inflammatory cytokines such as TNF and IL-1β. While Cg-induced TNF production/secretion depends on TLR4/MyD88 signaling, the production of pro-IL-1β relies on TLR4/TRIF/SYK/reactive oxygen species (ROS) signaling pathway. The maturation of pro-IL1β into IL-1β is dependent on canonical NLRP3 inflammasome activation via Pannexin-1/P2X7/K+ efflux signaling. In vivo, Cg-induced colitis was reduced in mice in the absence of NLRP3 inflammasome components. In conclusion, we unravel a critical role of the NLRP3 inflammasome in Cg-induced pro-inflammatory cytokines production and colitis, which is an important discovery on the pro-inflammatory properties of this sulfated polysaccharide for pre-clinical studies. Carrageenan (Cg) is one the most used flogistic stimulus in preclinical studies. Nevertheless, the molecular basis of Cg-induced inflammation is not totally elucidated. Herein, Lopes et al. unraveled the molecular basis for Cg-induced macrophages production of biological active IL-1β. The Cg-stimulated macrophages produces pro-IL-1β depends on TLR4/TRIF/Syk/ROS, whereas its processing into mature IL-1β is dependent on the canonical NLRP3 inflammasome.

中文翻译:

角叉菜胶诱导巨噬细胞产生细胞因子的分子基础。

低分子量卡拉胶 (Cg) 是一种源自海藻的硫酸化多糖,在临床前研究中广泛用作炎症刺激剂。然而,Cg 诱导炎症的分子机制尚未完全阐明。本研究旨在探讨 Cg 诱导巨噬细胞活化和细胞因子产生的分子基础。用 Kappa Cg 刺激小鼠腹膜巨噬细胞的原代培养物。上清液和细胞裂解液用于ELISA、蛋白质印迹、免疫荧光。Cg 诱导的小鼠结肠炎也被开发出来。在这里,我们发现 Cg 激活腹膜巨噬细胞产生促炎细胞因子,如 TNF 和 IL-1β。Cg 诱导的 TNF 产生/分泌取决于 TLR4/MyD88 信号传导,而 pro-IL-1β 的产生则依赖于 TLR4/TRIF/SYK/活性氧 (ROS) 信号传导途径。pro-IL1β 成熟为 IL-1β 依赖于通过 Pannexin-1/P2X7/K+ 外排信号传导的经典 NLRP3 炎性体激活。在体内,在缺乏 NLRP3 炎性体成分的小鼠中,Cg 诱导的结肠炎减少。总之,我们揭示了 NLRP3 炎症小体在 Cg 诱导的促炎细胞因子产生和结肠炎中的关键作用,这是临床前研究中这种硫酸多糖促炎特性的重要发现。卡拉胶 (Cg) 是临床前研究中最常用的弗洛西斯刺激物之一。然而,Cg 诱导炎症的分子基础尚未完全阐明。在此,洛佩斯等人。揭示了 Cg 诱导巨噬细胞产生生物活性 IL-1β 的分子基础。Cg 刺激的巨噬细胞产生 pro-IL-1β 取决于 TLR4/TRIF/Syk/ROS,而其加工成成熟 IL-1β 则取决于典型的 NLRP3 炎性体。
更新日期:2020-09-08
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