Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms

促炎细胞因子 炎症 重编程 药理学 免疫系统 关节炎 类风湿性关节炎 细胞因子 巨噬细胞 消炎药 癌症研究 医学 免疫学 化学 细胞 生物化学 体外
作者
Na Jia,Yunzhen Gao,Min Li,Yi Liang,Yuwen Li,Yunzhu Lin,Shiqi Huang,Qing Lin,Xun Sun,Qin He,Yuqin Yao,Ben Zhang,Zhirong Zhang,Ling Zhang
出处
期刊:Signal Transduction and Targeted Therapy [Springer Nature]
卷期号:8 (1) 被引量:28
标识
DOI:10.1038/s41392-023-01499-0
摘要

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.
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