W125 - Increased TGFRI Signaling Within Fibroblasts Contributes to Chronic Intestinal Inflammation by Promoting Type 1 Immune Responses in Crohn Disease

Abstract Text:

Background: Crohn’s disease (CD) is a multifactorial disease involving an abnormal immune response to gut microbiota in genetically susceptible individuals, resulting in chronic inflammation. The dysregulation of TGFβ signaling is involved CD-associated immunopathogenesis. Increase in the expression of TGFβ receptor 1 (TGFBR1) on fibroblasts in CD-involved tissue was previously reported. However, the role of increased fibroblast-restricted TGFβR1 signaling in CD-associated inflammation remains unclear. Thus, the objective of this study was to evaluate how increased signaling through TGFRI within fibroblasts contributes to the pathogenesis in CD-relevant murine models of colitis.

Methods: Gain-of-function with a constitutively active (CA) TGFBR1 was conditionally induced in fibroblasts by a Col1a promoter-mediated Cre recombinase (TGFBR1ca-Fib) in mice during a chronic DSS colitis model.

Results: Analysis of publicly available scRNAseq data demonstrated an increase in TGFBR1 expression within inflammatory fibroblasts in CD. We observed that in vivo overexpression of TGFBR1 in intestinal fibroblasts leads to an abnormal tissue architecture, with increased collagen deposition in the submucosal and mucosal layers in murine colons. Transcriptomic analysis (bulkRNAseq) of TGFBR1ca-Fib mice colonic tissue demonstrated a significant enrichment of the genes and pathways involved in matrix deposition, as well as activation of immune response pathways with enrichment of adaptive immune response pathways. Furthermore, we demonstrated that hyperactivation of TGFβ signaling in fibroblasts prior to induction of chronic DSS colitis significantly aggravated intestinal inflammation, increasing mRNA expression of IFNγ.

Conclusions: Collectively, our findings suggest that abnormal activation of TGFβR1 pathways within intestinal fibroblasts contributes to the type I inflammatory responses in CD.