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Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis
Wen Sun1,2, Hengwei Zhang2, Hua Wang1,2
1Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.
Abstract:
Expression levels 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. Intraarticular injection of Hes1-GFP/TNF-Tg or Hes1-GFP+ BM macrophages into WT and TNF-Tg mice showed the highest synovial GFP+ cells in the TNF-Tg mice that received Hes1-GFP/TNF-Tg cells. Thapsigargin (THAP), 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. THAP 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 them may represent a new therapeutic approach for patients with inflammatory arthritis. © 2017 American Society for Bone and Mineral Research.
Insights
Notch signaling is active in inflammatory macrophages (M1s) within the synovium of rheumatoid arthritis (RA) mouse models. Inhibiting Notch reduces M1s and joint inflammation, suggesting M1s are key drivers and potential therapeutic targets in inflammatory arthritis.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Rheumatoid arthritis (RA) is characterized by synovial inflammation.
- Notch signaling molecules are upregulated in RA synovium.
- The specific cell types and pathogenetic roles of Notch activation in RA remain unclear.
Purpose of the Study:
- To investigate the role of Notch-activated cells in rheumatoid arthritis pathogenesis.
- To identify the cell types exhibiting Notch activation in the inflamed synovium of TNF-transgenic (TNF-Tg) mice.
- To explore the therapeutic potential of targeting Notch signaling in inflammatory arthritis.
Main Methods:
- Utilized Hes1-GFP/TNF-transgenic (TNF-Tg) mice to track Notch-activated cells (GFP+).
- Analyzed synovial tissue from Hes1-GFP/TNF-Tg mice and performed bone marrow transplantation experiments.
- Administered Thapsigargin (THAP), a Notch inhibitor, to assess its effects on M1/M2 macrophage populations and joint pathology.
Main Results:
- GFP+ cells, indicative of Notch activation, were significantly increased in the synovium of Hes1-GFP/TNF-Tg mice.
- Approximately 60% of GFP+ cells were identified as F4/80+ macrophages expressing the M1 inflammatory marker.
- Bone marrow-derived M1 macrophages were the primary Notch-activated cells in the inflamed synovium.
- Notch inhibition with THAP reduced M1 macrophages, decreased joint lesions, and lowered GFP+ cell counts in TNF-Tg mice.
Conclusions:
- Activated Notch signaling in rheumatoid arthritis synovium is primarily associated with M1 macrophages of bone marrow origin.
- Targeting Notch-activated M1 macrophages presents a potential novel therapeutic strategy for inflammatory arthritis.
- Further research into Notch signaling pathways in inflammatory arthritis is warranted.
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