OBJECTIVE: To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)-induced arthritis. METHODS: SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R-deficient (IL-17R-/-) mice. At different time points, joint inflammation was assessed by using calipers to measure joint swelling. On day 42, mice were killed, and knee joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R-/- mice after 5 repeated injections of SCW fragments. RESULTS: IL-17R signaling did not play a significant role in acute joint swelling induced by a single injection of SCW fragments directly into the joint. However, repeated local injections of SCW fragments into the knee joints of IL-17R-/- mice resulted in fewer infiltrating cells in the joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL-17R-/- mice. Quantitative PCR analysis revealed impaired synovial expression of IL-1, IL-6, cyclooxygenase 2, stromelysin (MMP-3), gelatinase B (MMP-9), and collagenase 3 (MMP-13) in IL-17R-/- mice. CONCLUSION: These data show a critical role of IL-17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL-1 and different MMPs, during progression from an acute, macrophage-driven joint inflammation to a chronic, cartilage-destructive, T cell-mediated synovitis. Prevention of IL-17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.
OBJECTIVE: To examine the role of interleukin-17 receptor (IL-17R) signaling in cartilage destruction and its interrelationship with synovial IL-1 expression during chronic reactivated streptococcal cell wall (SCW)-induced arthritis. METHODS: SCW arthritis was repeatedly induced in wild-type (WT) and IL-17R-deficient (IL-17R-/-) mice. At different time points, joint inflammation was assessed by using calipers to measure joint swelling. On day 42, mice were killed, and knee joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL-17R-/- mice after 5 repeated injections of SCW fragments. RESULTS:IL-17R signaling did not play a significant role in acute joint swelling induced by a single injection of SCW fragments directly into the joint. However, repeated local injections of SCW fragments into the knee joints of IL-17R-/- mice resulted in fewer infiltrating cells in the joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL-17R-/- mice. Quantitative PCR analysis revealed impaired synovial expression of IL-1, IL-6, cyclooxygenase 2, stromelysin (MMP-3), gelatinase B (MMP-9), and collagenase 3 (MMP-13) in IL-17R-/- mice. CONCLUSION: These data show a critical role of IL-17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL-1 and different MMPs, during progression from an acute, macrophage-driven joint inflammation to a chronic, cartilage-destructive, T cell-mediated synovitis. Prevention of IL-17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.
Authors: Gilad Halpert; Tom Eitan; Elena Voronov; Ron N Apte; Lea Rath-Wolfson; Michael Albeck; Yona Kalechman; Benjamin Sredni Journal: J Biol Chem Date: 2014-04-24 Impact factor: 5.157