Shift from toll-like receptor 2 (TLR-2) toward TLR-4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR-4-mediated interleukin-17 production.
OBJECTIVE
Toll-like receptors (TLRs) may activate innate and adaptive immune responses in rheumatoid arthritis (RA) through recognition of microbial as well as endogenous ligands that have repeatedly been found in arthritic joints. The objective of this study was to investigate the involvement of TLR-2 and TLR-4 in the development of chronic destructive streptococcal cell wall (SCW)-induced arthritis, in which interleukin-1 (IL-1)/IL-17-dependent T cell-driven pathologic changes replace the macrophage-driven acute phase.


METHODS
Chronic SCW arthritis was induced by 4 repeated intraarticular injections of SCW fragments in wild-type, TLR-2(-/-), and TLR-4(-/-) mice. Clinical, histopathologic, and immunologic parameters of arthritis were evaluated.


RESULTS
The TLR-2 dependency of joint swelling during the acute phase was shifted to TLR-4 dependency during the chronic phase. Persistent joint inflammation in the latter phase of the model was significantly suppressed in TLR-4(-/-) mice. In the chronic phase, TLR-4 actively contributed to matrix metalloproteinase (MMP)-mediated cartilage destruction and to osteoclast formation, since the expression of the MMP-specific aggrecan neoepitope VDIPEN and the osteoclast marker cathepsin K was significantly reduced in TLR-4(-/-) mice. Furthermore, TLR-4(-/-) mice expressed less IL-1beta, tumor necrosis factor alpha, IL-6, and IL-23, cytokines that are implicated in IL-17 production. Accordingly, SCW-specific IL-17 production was found to be dependent on TLR-4 activation, since T cells from arthritic TLR-4(-/-) mice produced markedly less IL-17 upon SCW stimulation, whereas interferon-gamma production remained unaffected.


CONCLUSIONS
These data indicate the involvement of TLR-4 in the chronicity and erosive character of arthritis coincident with the antigen-specific IL-17 response. The high position of TLR-4 in the hierarchy of erosive arthritis provides an interesting therapeutic target for RA.
Abdollahi-Roodsaz
Shahla
S
Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. s.abdollahi-roodsaz@reuma.umcn.nl
Joosten
Leo A B
LA
Helsen
Monique M
MM
Walgreen
Birgitte
B
van Lent
Peter L
PL
van den Bersselaar
Liduine A
LA
Koenders
Marije I
MI
van den Berg
Wim B
WB
D000818:Animals; D001170:Arthritis, Infectious / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D001842:Bone and Bones / Q000473:pathology; D002356:Cartilage / Q000473:pathology; D019902:Chondrocytes / 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; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000378:metabolism; D013291:Streptococcus; D013583:Synovial Membrane / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D001425:Bacterial Outer Membrane Proteins; D015415:Biomarkers; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha