T cell dependence of chronic destructive murine arthritis induced by repeated local activation of Toll-like receptor-driven pathways: crucial role of both interleukin-1beta and interleukin-17.
OBJECTIVE
The pathogenesis of rheumatoid arthritis is often linked to bacterial infections. The present study was undertaken to develop a mouse model of chronic destructive arthritis induced by repeated intraarticular (IA) exposure to bacterial cell wall fragments and to investigate the cytokine dependence of this model.


METHODS
Mice that were deficient in various cytokines were injected IA with cell wall fragments of Streptococcus pyogenes on days 0, 7, 14, and 21. The development of chronic destructive arthritis was compared between groups of mice lacking different cytokines, to assess which cytokines were crucial for development of chronic destructive arthritis.


RESULTS
Repeated exposure of a joint to S pyogenes cell wall fragments resulted in the development of chronic destructive arthritis. In mice deficient in recombination-activating gene 2, streptococcal cell wall (SCW)-directed T cell reactivity was found and chronic arthritis did not develop, implicating T cells in the generation of chronic SCW-induced arthritis. Interleukin-17 (IL-17) receptor-deficient mice showed a reduction of joint destruction in the chronic stage, implicating a detrimental role of the recently discovered IL-17-producing T helper cells (Th17 cells). IL-23 expression was apparent during the late stages of arthritis. Joint swelling was no longer dependent on tumor necrosis factor alpha (TNFalpha) after the last flare, and pronounced cartilage damage was found after 28 days in TNFalpha-deficient mice. In contrast, IL-1beta-deficient mice were fully protected against joint swelling and cartilage and bone destruction during the late stages of disease.


CONCLUSIONS
These findings indicate that the TNFalpha dependence of arthritis is lost during the erosive stage, when Th17 cells become crucial. IL-1beta dependence remains strong, consistent with its pivotal role in the generation of Th17 cells.
Joosten
Leo A B
LA
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. l.joosten@reuma.umcn.nl
Abdollahi-Roodsaz
Shahla
S
Heuvelmans-Jacobs
Marleen
M
Helsen
Monique M A
MM
van den Bersselaar
Liduine A M
LA
Oppers-Walgreen
Birgitte
B
Koenders
Marije I
MI
van den Berg
Wim B
WB
D000208:Acute Disease; D000818:Animals; D001170:Arthritis, Infectious / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology / Q000494:pharmacology; D002356:Cartilage / Q000276:immunology / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013297:Streptococcus pyogenes / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D001425:Bacterial Outer Membrane Proteins; D020381:Interleukin-17; D053583:Interleukin-1beta; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha