title: Toll-like receptor 4 in bone marrow-derived cells as well as tissue-resident cells participate in aggravating autoimmune destructive arthritis.
abstract: OBJECTIVE
  A prominent role of Toll-like receptor 4 (TLR4) in arthritis is emerging. TLR4 is functional in immune cells and stromal cells. The aim was to investigate the involvement of TLR4 in bone marrow (BM)-derived and resident cells in arthritis.
  
  
  METHODS
  Reciprocal sex-mismatched BM transplantation was performed between IL-1Ra(-/-)TLR4(+/+) and IL-1Ra(-/-)TLR4(-/-) double knockout animals in Balb/c background. Arthritis was assessed macroscopically and by histopathology. Immunity was evaluated by splenic cytokine production and flow cytometry in draining lymph node (DLN) cells.
  
  
  RESULTS
  Arthritis progression was reduced to a similar extent in animals lacking TLR4 on BM-derived, resident cells or both. Histology revealed that joint inflammation was partially TLR4-dependent in either BM-derived or resident cells. TLR4 plays an additive role in BM-derived and resident cells in promoting cartilage erosion. By contrast, TLR4 was equally important in BM-derived and resident cells in mediating bone erosion. Systemically, TLR4 in both BM-derived and resident cells contributed to IL-17 production by splenic T-cells, whereas in the DLNs of arthritic joints this was not the case. Interestingly, in DLN, the dominant cells producing IL-17 were CD4 negative, and cell numbers were determined by TLR4 in the BM-derived cells.
  
  
  CONCLUSIONS
  TLR4 is necessary in both BM-derived and resident cells for full-blown joint swelling, inflammation and bone erosion. Furthermore, TLR4 on BM-derived and tissue-resident cells show an additive effect in cartilage destruction. Interestingly, TLR4 on BM-derived and tissue-resident cells are both required for IL-17 production in spleen, but only in BM-derived cells in DLN.
authors.affiliation: Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Ben T
authors.initials: BT
authors.lastname: van den Brand
authors.forename: Shahla
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.forename: Miranda B
authors.initials: MB
authors.lastname: Bennink
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Onno J
authors.initials: OJ
authors.lastname: Arntz
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002358:Cartilage, Articular / Q000473:pathology; D005260:Female; D020381:Interleukin-17 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013154:Spleen / Q000378:metabolism; D013264:Stifle / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Arthritis; Autoimmunity; Cytokines; Inflammation; T Cells