Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis.
Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis.
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靶向Notch激活的M1巨噬细胞可减轻炎症性关节炎小鼠模型中的关节组织损伤
DOI：
10.1002/jbmr.3117
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发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Xing L
中科院分区：
文献类型：
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作者：
Sun W;Zhang H;Wang H;Chiu YG;Wang M;Ritchlin CT;Kiernan A;Boyce BF;Xing L
Notch信号分子在类风湿性关节炎（RA）患者滑膜中的表达增加。然而，目前尚不清楚RA滑膜中哪些细胞类型具有Notch激活，或者它们是否在RA中起致病作用。在这里，我们使用Hes 1-GFP/TNF-转基因（TNF-Tg）小鼠研究具有活性Notch信号（GFP+）的细胞在RA中的作用。Hes 1-GFP/TNF-Tg小鼠滑膜中GFP+细胞的数量显著增加，其中约60%是表达炎性巨噬细胞（M1）标志物的F4/80+巨噬细胞。移植Hes 1-GFP/TNF-Tg骨髓（BM）的TNF-Tg小鼠在其滑膜中比在BM中具有显著更多的GFP+细胞。将Hes 1-GFP/TNF-Tg或Hes 1-GFP+ BM巨噬细胞关节内注射到WT和TNF-Tg小鼠中，在接受Hes 1-GFP/TNF-Tg细胞的TNF-Tg小鼠中显示出最高的滑膜GFP+细胞。Thapsigargin是一种Notch抑制剂，可减少TNF诱导的M1，增加M2数量，减少Hes 1-GFP/TNF-Tg小鼠关节病变、滑膜M1和GFP+细胞。Thapsigargin不影响携带组成型活性Notch 1的小鼠的M1。因此，在TNF-Tg小鼠的发炎滑膜中具有活化的Notch信号传导的主要细胞是来自BM的M1，并且靶向这可能代表炎性关节炎患者的新治疗方法。
Expression of Notch signaling molecules are increased in synovium from patients with rheumatoid arthritis (RA). However, it is not known which cell type(s) in RA synovium have Notch activation or if they play a pathogenetic role in RA. Here, we used Hes1-GFP/TNF-transgenic (TNF-Tg) mice to investigate the role of cells with active Notch signaling (GFP+) in RA. The number of GFP+ cells was significantly increased in synovium in Hes1-GFP/TNF-Tg mice and about 60% of them were F4/80+ macrophages expressing the inflammatory macrophage (M1) marker. TNF-Tg mice transplanted with Hes1-GFP/TNF-Tg bone marrow (BM) had significantly more GFP+ cells in their synovium than in BM. Intra-articular injection of Hes1-GFP/TNF-Tg or Hes1-GFP+ BM macrophages into WT and TNF-Tg mice showed highest synovial GFP+ cells in the TNF-Tg mice received Hes1-GFP/TNF-Tg cells. Thapsigargin, a Notch inhibitor, decreased TNF-induced M1 and increased M2 numbers and reduced joint lesion, synovial M1s and GFP+ cells in Hes1-GFP/TNF-Tg mice. Thapsigargin did not affect M1s from mice carrying a constitutively active Notch1. Thus, the main cells with activated Notch signaling in the inflamed synovium of TNF-Tg mice are M1s derived from BM and targeting which may represent a new therapeutic approach for patients with inflammatory arthritis.