Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo

Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15 ) is implicated in inflammatory bowel disease, modulating the location and severity of inflammation and fibrosis. TL1A expression is increased in inflamed mucosa and associated with fibrostenosing Crohn’s disease. Tl1a-overexpression in mice causes spontaneous ileitis, and exacerbates induced proximal colitis and fibrosis. Intestinal fibroblasts express Death-receptor 3 (DR3; the only know receptor for TL1A) and stimulation with TL1A induces activation in vitro. However, the contribution of direct TL1A-DR3 activation on fibroblasts to fibrosis in vivo remains unknown. TL1A overexpressing naïve T cells were transferred into Rag −/− , Rag −/− mice lacking DR3 in all cell types ( Rag −/− Dr3 −/− ), or Rag −/− mice lacking DR3 only on fibroblasts ( Rag −/− Dr3 ∆Col1a2 ) to induce colitis and fibrosis, assessed by clinical disease activity index, intestinal inflammation, and collagen deposition. Rag −/− mice developed overt colitis with intestinal fibrostenosis. In contrast, Rag −/− Dr3 −/− demonstrated decreased inflammation and fibrosis. Despite similar clinical disease and inflammation as Rag −/− , Rag −/− Dr3 ∆Col1a2 exhibited reduced intestinal fibrosis and attenuated fibroblast activation and migration. RNA-Sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major pathway activated by TL1A and inhibition of this pathway modulated TL1A-mediated fibroblast functions. Thus, direct TL1A signaling on fibroblasts promotes intestinal fibrosis in vivo. These results provide novel insight into profibrotic pathways mediated by TL1A paralleling its pro-inflammatory effects.