Abstract
There have been many attempts to visualize the inflamed joints using multiphoton microscopy. However, due to the hypervascular and multilayered structure of the inflamed synovium, intravital imaging of the deep synovial tissue has been difficult. Here, we established original intravital imaging systems to visualize synovial tissue and pathological osteoclasts at the pannus–bone interface using multiphoton microscopy. Combined with fluorescence-labeling of CTLA-4 Ig, a biological agent used for the treatment of rheumatoid arthritis, we identified that CTLA-4 Ig was distributed predominantly within the inflamed synovium and bound to CX3CR1+ macrophages and CD140a+ fibroblasts 6 h after injection, but not to mature osteoclasts. Intravital imaging of blood and lymphatic vessels in the inflamed synovium further showed that extravasated CTLA-4 Ig was immediately drained through lymphatic vessels under acute arthritic conditions, but the drainage activity was retarded under chronic conditions. These results indicate that this intravital synovial imaging system can serve as a platform for exploring the dynamics of immune cells, osteoclasts, and biological agents within the synovial microenvironment in vivo.
Highlights
There have been many attempts to visualize the inflamed joints using multiphoton microscopy
Previous studies reported that osteoclasts express B710 and CTLA-4 Ig suppresses osteoclastogenesis[8], but it remains unclear whether CTLA-4 Ig directly binds to and exerts its effect against mature osteoclasts formed at the pannus-bone interface
The mean permeability index of the 3-h observation was comparable between acute and chronic collagen-induced arthritis (CIA) mice in the interstitial space, that in lymphatic vessels was higher in acute CIA mice. These results indicated that the drainage capacity of lymphatic vessels in the synovium differs between acute and chronic arthritic conditions, which may affect the dynamics of CTLA-4 Ig within the synovial microenvironment
Summary
There have been many attempts to visualize the inflamed joints using multiphoton microscopy. Intravital imaging of blood and lymphatic vessels in the inflamed synovium further showed that extravasated CTLA-4 Ig was immediately drained through lymphatic vessels under acute arthritic conditions, but the drainage activity was retarded under chronic conditions These results indicate that this intravital synovial imaging system can serve as a platform for exploring the dynamics of immune cells, osteoclasts, and biological agents within the synovial microenvironment in vivo. We developed an intravital imaging system using multiphoton microscopy to directly visualize immune cells, pathological osteoclasts, and CTLA-4 Ig in the inflamed synovium. We combined this system with flow cytometry (FCM) to investigate the dynamics and target cells of CTLA-4 Ig within the synovial microenvironment under arthritic conditions
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