与正常滑膜相比，类风湿性关节炎 (RA) 中的 Notch 配体和受体（包括 JAG1/2、DLL1/4 和 Notch1/3）在巨噬细胞 (MΦs)、成纤维细胞样滑膜细胞 (FLS) 和/或内皮细胞上富集组织（ST）。能量多普勒超声引导 ST 研究表明，Notch 家族与早期活动性 RA 密切相关，尤其是在新血管形成期间。相比之下，Notch 家族在糜烂阶段并未涉及，其与 RA ST 中放射学损伤缺乏相关性就证明了这一点。 TLR 和 TNF 是 RA MΦ、FLS 和内皮细胞中 Notch 表达的常见诱导剂。在Notch配体中，JAG1和/或DLL4最容易被RA MΦ或内皮细胞中的炎症反应诱导，并反式激活它们在RA FLS上的受体。 TNF 对 Notch 配体起着核心作用，因为抗 TNF 良好反应者在 RA ST 骨髓细胞中表现出 JAG1/2 和 DLL1/4 转录下调。在体外研究中，TNF 增加 MΦ 中 Notch3 的表达，并通过添加 RA FLS 进一步放大。特定疾病缓解抗风湿药物 (DMARD) 降低了 MΦ 和 RA FLS 共培养物中 JAG1 和 Notch3 的表达。含有 FLS 和内皮细胞的类器官增加了 JAG1 和 Notch3 的表达。尽管如此，甲氨蝶呤、IL-6R 抗体和 B 细胞阻滞剂在降低 Notch 家族表达方面大多无效。 NF-κB、MAPK 和 AKT 通路参与 Notch 信号传导，而 JAK/STAT 则不参与。尽管Notch阻断在RA临床前研究中有效，但其小分子抑制剂在I期和II期研究中失败，这表明可能需要替代策略来拦截其功能。本文受版权保护。版权所有。

Notch ligands and receptors, including JAG1/2, DLL1/4, and Notch1/3, are enriched on macrophages (MΦs), fibroblast-like synoviocytes (FLS), and/or endothelial cells in rheumatoid arthritis (RA) compared to normal synovial tissues (ST). Power Doppler ultrasound-guided ST studies reveal that the Notch family is highly involved in early active RA, especially during neovascularization. In contrast, the Notch family is not implicated during the erosive stage, evidenced by their lack of correlation with radiographic damage in RA STs. TLRs and TNF are the common inducers of Notch expression in RA MΦs, FLS, and endothelial cells. Among Notch ligands, JAG1 and/or DLL4 are most inducible by inflammatory responses in RA MΦs or endothelial cells and trans-activate their receptors on RA FLS. TNF plays a central role on Notch ligands, as anti-TNF good responders display JAG1/2 and DLL1/4 transcriptional downregulation in RA ST myeloid cells. In in vitro studies, TNF increases Notch3 expression in MΦs, which is further amplified by RA FLS addition. Specific disease-modifying anti-rheumatic drugs (DMARDs) reduced JAG1 and Notch3 expression in MΦ and RA FLS cocultures. Organoids containing FLS and endothelial cells have increased expression of JAG1 and Notch3. Nonetheless, Methotrexate, IL-6R antibodies, and B cell blockers are mostly ineffective at decreasing Notch family expression. NF-κB, MAPK, and AKT pathways are involved in Notch signaling, whereas JAK/STATs are not. Although Notch blockade has been effective in RA preclinical studies, its small molecule inhibitors have failed in phase I and II studies, suggesting that alternative strategies may be required to intercept their function.This article is protected by copyright. All rights reserved.