Jesse Brown VA Medical Center, Chicago, Illinois, USA.
Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA.
Ann Rheum Dis. 2023 Apr;82(4):483-495. doi: 10.1136/ard-2022-223284. Epub 2023 Jan 2.
Syntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA.
RA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape.
Syntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14CD86GLUT1MΦs reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80iNOSRAPTORMΦs represent glycolytic RA MΦs, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1 animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated MΦ remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation.
The syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract).
新型内源性配体 syntenin-1 在类风湿关节炎 (RA) 标本中比骨关节炎滑液和正常滑膜组织 (ST) 更为丰富。然而，RA 中 syntenin-1 的细胞来源、免疫调节和分子机制尚不清楚。
使用 RA 患者的髓系和淋巴样细胞以及临床前模型来研究 syntenin-1/syndecan-1 对炎症和代谢景观的影响。
syntenin-1 和 syndecan-1 (SDC-1) 在 RA ST 巨噬细胞 (MΦ) 和内皮细胞上共定位。有趣的是，血液 syntenin-1 和 ST SDC-1 转录组与环瓜氨酸肽、红细胞沉降率、ST 厚度和骨侵蚀相关。syntenin-1 重编程的代谢性 CD14CD86GLUT1MΦ 表现出广泛的促炎干扰素转录因子、单核因子和糖酵解因子，同时伴有氧化中间产物减少，SDC-1 阻断、葡萄糖摄取和/或 mTOR 信号通路可下调这些中间产物。相反，IL-5R 和 PDZ1 抑制对 syntenin-1 重编程的 RA MΦ 无效。在 syntenin-1 诱导的关节炎中，F4/80iNOSRAPTORMΦ 代表糖酵解 RA MΦ，通过放大炎症和糖酵解网络。在 SDC-1 动物中，这些网络被阻断，而关节促修复单核因子不受影响，氧化代谢物适度补充。在 RA 细胞和/或临床前模型中，syntenin-1 诱导的关节炎发病机制依赖于 mTOR 激活的 MΦ 重塑及其通过诱导 IL-12 和 IL-18 交叉调节 Th1 细胞的能力。此外，暴露于 syntenin-1 的 RA 和关节髓样细胞通过 SDC-1 连接和 RANK、CTSK 和 NFATc1 转录上调被诱导转化为破骨细胞。
syntenin-1/SDC-1 途径通过糖酵解 MΦ 和 Th1 细胞交叉调节在 RA 的炎症和代谢景观中发挥关键作用（示意图）。
