Interleukin-17 receptor deficiency results in impaired synovial expression of interleukin-1 and matrix metalloproteinases 3, 9, and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall-induced 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.


CONCLUSIONS
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.
Koenders
Marije I
MI
University Medical Center St. Radboud, Nijmegen, The Netherlands.
Kolls
Jay K
JK
Oppers-Walgreen
Birgitte
B
van den Bersselaar
Liduine
L
Joosten
Leo A B
LA
Schurr
Jill R
JR
Schwarzenberger
Paul
P
van den Berg
Wim B
WB
Lubberts
Erik
E
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology*; D002356:Cartilage / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016923:Cell Death; D019902:Chondrocytes / Q000473:pathology / Q000502:physiology; D002908:Chronic Disease; D017364:Collagenases / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D007375:Interleukin-1 / Q000235:genetics*; D020381:Interleukin-17 / Q000235:genetics*; D008297:Male; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D013291:Streptococcus / Q000276:immunology; D013583:Synovial Membrane / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D000945:Antigens, Differentiation, T-Lymphocyte; C098680:Il17a protein, mouse; D007375:Interleukin-1; D020381:Interleukin-17; D012333:RNA, Messenger; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9