Requirement of IL-17 receptor signaling in radiation-resistant cells in the joint for full progression of destructive synovitis.
IL-17 is a proinflammatory cytokine suspected to be involved in inflammatory and autoimmune diseases such as rheumatoid arthritis. In the present study, we report that IL-17R signaling is required in radiation-resistant cells in the joint for full progression of chronic synovitis and bone erosion. Repeated injections of Gram-positive bacterial cell wall fragments (streptococcal cell wall) directly into the knee joint of naive IL-17R-deficient (IL-17R-/-) mice had no effect on the acute phase of arthritis but prevented progression to chronic destructive synovitis as was noted in wild-type (wt) mice. Microarray analysis revealed significant down-regulation of leukocyte-specific chemokines, selectins, cytokines, and collagenase-3 in the synovium of IL-17R-/- mice. Bone marrow (BM) chimeric mice revealed the need for IL-17R expression on radiation-resistant joint cells for destructive inflammation. Chimeric mice of host wt and donor IL-17R-/- BM cells developed destructive synovitis in this chronic reactivated streptococcal cell wall arthritis model similar to wt-->wt chimeras. In contrast, chimeric mice of host IL-17R-/- and donor wt BM cells were protected from chronic destructive arthritis similar as IL-17R-/- -->IL-17R-/- chimeras. These data strongly indicate that IL-17R signaling in radiation-resistant cells in the joint is required for turning an acute macrophage-mediated inflammation into a chronic destructive synovitis.
Lubberts
Erik
E
Department of Medicine, Gene Therapy Program, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. E.Lubberts@erasmusmc.nl
Schwarzenberger
Paul
P
Huang
Weitao
W
Schurr
Jill R
JR
Peschon
Jacques J
JJ
van den Berg
Wim B
WB
Kolls
Jay K
JK
D000818:Animals; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D018450:Disease Progression; D005260:Female; D007375:Interleukin-1 / Q000502:physiology; D007719:Knee Joint / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011836:Radiation Tolerance; D018123:Receptors, Interleukin / Q000502:physiology*; D053722:Receptors, Interleukin-17; D019087:Selectins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D013585:Synovitis / Q000209:etiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D018925:Chemokines; D016207:Cytokines; C491673:Il17ra protein, mouse; D007375:Interleukin-1; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D019087:Selectins; D014409:Tumor Necrosis Factor-alpha