title: Ligation of TLR5 promotes myeloid cell infiltration and differentiation into mature osteoclasts in rheumatoid arthritis and experimental arthritis.
abstract: Our aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation, and in addition, to uncover the significance of TNF-α function in TLR5-mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen-induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, we used anti-TLR5 Ab therapy in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-α production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-α, because inhibition of both pathways can more strongly impair RA synovial fluid-driven monocyte migration and osteoclast differentiation compared with each factor alone. In preclinical studies, flagellin postonset treatment in CIA and local TLR5 ligation in vivo provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-α cascade. Conversely, CIA joint inflammation and bone erosion are alleviated when TLR5 function is blocked. We found that TLR5 and TNF-α pathways are interconnected, because TNF-α is produced by TLR5 ligation in RA myeloid cells, and anti-TNF-α therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct and an indirect mechanism are involved in TLR5-driven RA inflammation and bone destruction.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Chamberlain
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: Abdul B
authors.initials: AB
authors.lastname: Essani
authors.affiliation: Department of Microbiology and Immunology, Midwestern University, Chicago College of Osteopathic Medicine, Downers Grove, IL 60515;
authors.forename: Michael V
authors.initials: MV
authors.lastname: Volin
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: M Asif
authors.initials: MA
authors.lastname: Amin
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: Suncica
authors.initials: S
authors.lastname: Volkov
authors.affiliation: Department of Medicine, University of Massachusetts Memorial Medical Center and University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Gravallese
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: Shiva
authors.initials: S
authors.lastname: Arami
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: William
authors.initials: W
authors.lastname: Swedler
authors.affiliation: University of California Davis Medical Center, Sacramento, CA 95817.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: Anjali
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612;
authors.forename: Nadera
authors.initials: N
authors.lastname: Sweiss
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612; shahrara@uic.edu.
authors.forename: Shiva
authors.initials: S
authors.lastname: Shahrara
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001169:Arthritis, Experimental / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D005260:Female; D005408:Flagellin / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D023461:Myeloid Progenitor Cells / Q000166:cytology* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D010010:Osteoclasts / Q000166:cytology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D053245:RANK Ligand / Q000096:biosynthesis; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis; D013582:Synovial Fluid / Q000166:cytology; D051198:Toll-Like Receptor 5 / Q000096:biosynthesis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D000906:Antibodies; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D051198:Toll-Like Receptor 5; D014409:Tumor Necrosis Factor-alpha; D005408:Flagellin; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases