Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases

• Published in: The Journal of experimental medicine Vol. 205; no. 2; pp. 331 - 337
• Main Authors: Armaka, Maria, Apostolaki, Maria, Jacques, Peggy, Kontoyiannis, Dimitris L, Elewaut, Dirk, Kollias, George
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 18.02.2008
• Subjects: Animals; Arthritis - immunology; Arthritis - pathology; Bone Marrow Transplantation; Brief Definitive Reports; Cells, Cultured; Fibroblasts - immunology; Ileum - pathology; Inflammation - immunology; Intestinal Diseases - immunology; Intestinal Diseases - pathology; Mesenchymal Stromal Cells - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Tumor Necrosis Factor, Type I - deficiency; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - immunology; Sacroiliac Joint - pathology; Tumor Necrosis Factors - genetics; Tumor Necrosis Factors - immunology
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20070906

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.