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

Abstract

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.

Whole-body deletion of LPS-induced TNF-α factor (LITAF) markedly improves experimental endotoxic shock and inflammatory arthritis

“…Our results indicate the importance of LITAF in cells (i.e., macrophages, lymphocytes, or fibroblasts) other than LysMCre-positive cells, as evidenced by a reduced responsiveness to endotoxic challenge obtained in tamLITAF (i) −/− mice than previously reported in our macLITAF −/− (15). However, other cells, in addition to macrophages, are involved in systemic inflammation and associated inflammatory pathways (18), yet no studies have examined the effect of whole-body LITAF deficiency on the response to inflammatory stimulants.…”

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

“…The Tnfrsf1a fl/fl mouse line was expanded, and the mice were backcrossed to C57BL/6J for at least 6 generations. After crossing the Tnfr sf1a fl/fl mice with deleter cre mice, the deficiency in p55TNFR expression in Tnfrsf1a Δ/Δ mice was confirmed in BMDMs by FACS analysis (Supplemental Figure 4C) as previously described (47).…”

Murine Models of Inflammatory Bowel Disease (IBD)

“…In contrast, driving TNFa overexpression in the myeloid compartment using LysM-cre was sufficient to cause ileitis comparable to a TNFDARE animal indicating that myeloid immune cells are an important mediator of disease (Kontoyiannis et al 2002). Finally, an additional study suggested that TNF receptor expression solely via the collagen VI promoter, restricting the ability to respond to TNF to the epithelial layer of the gut and other stromal tissues, was sufficient to induce disease (Armaka et al 2008). This model highlights the complex interplay between the various facets of an immune response-myeloid production, epithelial sensing, and an effector response mediated by CD8 T cells and the production of interferon-g all contribute to induce a disease process controlled by TNFa.…”