title: Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: critical role of myeloid differentiation factor 88.
abstract: The IL-1R/Toll-like receptor (TLR) superfamily of receptors has a key role in innate immunity and inflammation. In this study, we report that streptococcal cell wall (SCW)-induced joint inflammation is predominantly dependent on TLR-2 signaling, since TLR-2-deficient mice were unable to develop either joint swelling or inhibition of cartilage matrix synthesis. Myeloid differentiation factor 88 (MyD88) is a Toll/IL-1R domain containing adaptor molecule known to have a central role in both IL-1R/IL-18R and TLR signaling. Mice deficient for MyD88 did not develop SCW-induced arthritis; both joint swelling and disturbance of cartilage chondrocyte anabolic function was completely abolished. Local levels of proinflammatory cytokines and chemokines in synovial tissue washouts were strongly reduced in MyD88-deficient mice. Histology confirmed the pivotal role of MyD88 in acute joint inflammation. TLR-2-deficient mice still allow influx of inflammatory cells into the joint cavity, although the number of cells was markedly reduced. No influx of inflammatory cells was seen in joints of MyD88-deficient mice. In addition, cartilage matrix proteoglycan loss was completely absent in MyD88 knockout mice. These findings clearly demonstrated that MyD88 is a key component in SCW-induced joint inflammation. Since agonists of the Toll-like pathway are abundantly involved in both septic and rheumatoid arthritis, targeting of MyD88 may be a novel therapy in inflammatory joint diseases.
authors.affiliation: Rheumatology Research Laboratory and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. l.joosten@reuma.umcn.nl
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.forename: Ruben L
authors.initials: RL
authors.lastname: Smeets
authors.forename: Marleen
authors.initials: M
authors.lastname: Heuvelmans-Jacobs
authors.forename: Monique M A
authors.initials: MM
authors.lastname: Helsen
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism; D002473:Cell Wall / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007375:Interleukin-1 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family / Q000276:immunology; D053594:Myeloid Differentiation Factor 88; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D011509:Proteoglycans / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D018836:Inflammation Mediators; D007375:Interleukin-1; D020382:Interleukin-18; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha