Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases.
Tumor necrosis factor (TNF) is key to the pathogenesis of various arthritic diseases and inflammatory bowel disease (IBD). Anti-TNF therapies have proved successful in the clinical treatment of these diseases, but a mechanistic understanding of TNF function is still lacking. We have investigated early cellular mechanisms of TNF function in these diseases using an established TNF transgenic model, which develops a spondyloarthritis-like disease characterized by peripheral joint arthritis, sacroiliitis, enthesitis, and Crohn's-like IBD. Bone marrow grafting experiments demonstrated that development of arthritis requires TNF receptor I (TNFRI) expression in the radiation-resistant compartment, which is also known to be a sufficient target of TNF in the development of Crohn's-like IBD in the same model. Early activation of synovial fibroblasts and intestinal myofibroblasts could also be demonstrated by perturbed expression of matrix metalloproteases and their inhibitors. Notably, selective Cre/loxP-mediated TNFRI expression in mesenchymal cells resulted in a fully arthritic-spondyloarthritic and intestinal phenotype, indicating that mesenchymal cells are primary and sufficient targets of TNF in these pathologies. Our results offer a novel mechanistic perspective for TNF function in gut and joint pathologies and indicate early common cellular pathways that may also explain the often observed synovial-gut axis in human disease.
Armaka
Maria
M
Institute of Immunology, Biomedical Sciences Research Center (BSRC) Alexander Fleming, Vari 16672, Greece.
Apostolaki
Maria
M
Jacques
Peggy
P
Kontoyiannis
Dimitris L
DL
Elewaut
Dirk
D
Kollias
George
G
D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology; D007082:Ileum / Q000473:pathology; D007249:Inflammation / Q000276:immunology; D007410:Intestinal Diseases / Q000276:immunology* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012446:Sacroiliac Joint / Q000473:pathology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology*
D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D048069:Tumor Necrosis Factors