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Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2023-07-28 , DOI: 10.1038/s41392-023-01499-0
Na Jia 1 , Yunzhen Gao 1 , Min Li 1 , Yi Liang 1 , Yuwen Li 2 , Yunzhu Lin 1 , Shiqi Huang 1 , Qing Lin 1 , Xun Sun 1 , Qin He 1 , Yuqin Yao 1 , Ben Zhang 1 , Zhirong Zhang 1 , Ling Zhang 1
Affiliation  

Rheumatoid arthritis (RA) is a common chronic inflammatory disorder that usually affects joints. It was found that roburic acid (RBA), an ingredient from anti-RA herb Gentiana macrophylla Pall., displayed strong anti-inflammatory activity. However, its medical application is limited by its hydrophobicity, lack of targeting capability and unclear functional mechanism. Here, we constructed a pH responsive dual-target drug delivery system hitchhiking RBA (RBA-NPs) that targeted both CD44 and folate receptors, and investigated its pharmacological mechanism. In rat RA model, the nanocarriers effectively delivered RBA to inflammatory sites and significantly enhanced the therapeutic outcomes compared with free RBA, as well as strongly reducing inflammatory cytokine levels and promoting tissue repair. Following analysis revealed that M1 macrophages in the joints were reprogrammed to M2 phenotype by RBA. Since the balance of pro- and anti-inflammatory macrophages play important roles in maintaining immune homeostasis and preventing excessive inflammation in RA, this reprogramming is likely responsible for the anti-RA effect. Furthermore, we revealed that RBA-NPs drove M1-to-M2 phenotypic switch by down-regulating the glycolysis level via blocking ERK/HIF-1α/GLUT1 pathway. Thus, our work not only developed a targeting delivery system that remarkably improved the anti-RA efficiency of RBA, but also identified a potential molecular target to reversely reprogram macrophages though energy metabolism regulation.



中文翻译:

通过靶向递送的罗布酸对促炎巨噬细胞进行代谢重编程可有效改善类风湿性关节炎症状

类风湿性关节炎 (RA) 是一种常见的慢性炎症性疾病,通常影响关节。研究发现,抗 RA 草药Gentiana macrophylla Pall. 中的成分 Roburic Acid (RBA) 具有很强的抗炎活性。然而,其疏水性、缺乏靶向能力和作用机制尚不清楚,限制了其在医学上的应用。在此,我们构建了一种同时靶向 CD44 和叶酸受体的 pH 响应双靶点药物递送系统(RBA-NPs),并研究了其药理机制。在大鼠 RA 模型中,纳米载体有效地将 RBA 递送至炎症部位,与游离 RBA 相比显着增强了治疗效果,并强烈降低炎症细胞因子水平并促进组织修复。随后的分析表明,关节中的 M1 巨噬细胞被 RBA 重编程为 M2 表型。由于促炎和抗炎巨噬细胞的平衡在维持免疫稳态和防止 RA 过度炎症方面发挥着重要作用,因此这种重编程可能是抗 RA 作用的原因。此外,我们发现 RBA-NPs 通过阻断 ERK/HIF-1α/GLUT1 途径下调糖酵解水平,从而驱动 M1 到 M2 表型转换。因此,我们的工作不仅开发了一种显着提高 RBA 抗 RA 效率的靶向递送系统,而且还确定了通过能量代谢调节反向重编程巨噬细胞的潜在分子靶点。

更新日期:2023-07-28
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