title: Spatiotemporal expression of endogenous TLR4 ligands leads to inflammation and bone erosion in mouse collagen-induced arthritis.
abstract: Increased expression of endogenous Toll-like receptor 4 (TLR4) ligands (e.g., Tenascin-C, S100A8/A9, citrullinated fibrinogen (cFb) immune complexes) has been observed in patients with rheumatoid arthritis (RA). However, their roles in RA pathogenesis are not well understood. Here, we investigated the expression kinetics and role of endogenous TLR4 ligands in the murine model of collagen-induced arthritis (CIA). Tenascin-C was upregulated in blood early in CIA, and correlated positively with the clinical score at day 56. Levels of S100A8/A9 increased starting from day 28, peaking at day 42, and correlated positively with joint inflammation. Levels of anti-cFb antibodies increased during the late phase of CIA and correlated positively with both joint inflammation and cartilage damage. Blockade of TLR4 activation at the time of the first TLR4 ligand upregulation prevented clinical and histological signs of arthritis. A TLR4-dependent role was also observed for Tenascin-C and cFb immune complexes in osteoclast differentiation in vitro. Taken together, our data suggests that the pathogenic contribution of TLR4 in promoting joint inflammation and bone erosion during CIA occurs via various TLR4 ligands arising at different stages of disease. The data also suggests that Blockade of TLR4 with monoclonal antibodies is a promising strategy in RA treatment.
authors: NovImmune SA, Plan-Les-Ouates, Geneva, Switzerland.
authors: Gaëlle Wambiekele
authors: GW
authors: Kiyeko
authors: NovImmune SA, Plan-Les-Ouates, Geneva, Switzerland.
authors: Eric
authors: E
authors: Hatterer
authors: NovImmune SA, Plan-Les-Ouates, Geneva, Switzerland.
authors: Suzanne
authors: S
authors: Herren
authors: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Irene
authors: I
authors: Di Ceglie
authors: Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors: Peter L
authors: PL
authors: van Lent
authors: Department of Pathology and Immunology, University of Geneva, School of Medicine, Geneva, Switzerland.
authors: Walter
authors: W
authors: Reith
authors: NovImmune SA, Plan-Les-Ouates, Geneva, Switzerland.
authors: Marie
authors: M
authors: Kosco-Vilbois
authors: NovImmune SA, Plan-Les-Ouates, Geneva, Switzerland.
authors: Walter
authors: W
authors: Ferlin
authors: NovImmune SA, Plan-Les-Ouates, Geneva, Switzerland. lshang@novimmune.com.
authors: Limin
authors: L
authors: Shang
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000097:blood; D001169:Arthritis, Experimental / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000473:pathology*; D040501:Calgranulin A / Q000097:blood* / Q000235:genetics; D002454:Cell Differentiation; D003094:Collagen; D004195:Disease Models, Animal; D005340:Fibrinogen / Q000276:immunology; D007596:Joints / Q000276:immunology; D008024:Ligands; D051379:Mice; D008811:Mice, Inbred DBA; D010010:Osteoclasts / Q000378:metabolism; D062211:Spatio-Temporal Analysis; D019063:Tenascin / Q000097:blood* / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000936:Antigen-Antibody Complex; D040501:Calgranulin A; D008024:Ligands; C086145:S100a8 protein, mouse; D019063:Tenascin; D051197:Toll-Like Receptor 4; D005340:Fibrinogen; D003094:Collagen
keywords: Endogenous ligands; Monoclonal antibody; Osteoclasts; Rheumatoid arthritis; Toll-like receptor 4 (TLR4)