Cadherin-11 Is a Regulator of Intestinal Fibrosis

Eleonora Franzè, Ivan Monteleone, Federica Laudisi, Angelamaria Rizzo, Vincenzo Dinallo, Davide Di Fusco, Alfredo Colantoni, Angela Ortenzi, Paolo Giuffrida, Sara Di Carlo, Giuseppe S. Sica, Antonio Di Sabatino, Giovanni Monteleone

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Aims: Although the mechanisms underlying the formation of intestinal fibrostrictures in Crohn's disease [CD] are not fully understood, activation of fibroblasts and excessive collagen deposition are supposed to contribute to the development of such complications. Here, we investigated the role of cadherin-11 [CDH-11], a fibroblast-derived protein that induces collagen production in various organs, in intestinal fibrosis. Methods: CDH-11 expression was evaluated in inflammatory [I] and fibrostricturing [FS] CD mucosal samples, ulcerative colitis [UC] mucosal samples, and ileal and colonic control samples, by real-time polymerase chain reaction, western blotting, and immunohistochemistry. CDH-11 expression was evaluated in normal and in CD intestinal fibroblasts stimulated with inflammatory/fibrogenic cytokines. FS CD fibroblasts were cultured either with a specific CDH-11 antisense oligonucleotide [AS], or activating CDH-11 fusion protein and activation of RhoA/ROCK, and TGF-β pathways and collagen production were evaluated by western blotting. Finally, we assessed the susceptibility of CDH-11-knockout [KO] mice to colitis-induced intestinal fibrosis. Results: CDH-11 RNA and protein expression were increased in both CD and UC as compared with controls. In CD, the greater expression of CDH-11 was seen in FS samples. Stimulation of fibroblasts with TNF-α, interleukin [IL]-6, IFN-γ, IL-13, and IL-1β enhanced CDH-11 expression. Knockdown of CDH-11 in FS CD fibroblasts impaired RhoA/ROCK/TGF-β signalling and reduced collagen synthesis, whereas activation of CDH-11 increased collagen secretion. CDH-11 KO mice were largely protected from intestinal fibrosis. Conclusions: Data show that CDH-11 expression is up-regulated in inflammatory bowel disease [IBD] and suggest a role for this protein in the control of intestinal fibrosis.

Original languageEnglish
Pages (from-to)406-417
Number of pages12
JournalJournal of Crohn's and Colitis
Volume14
Issue number3
DOIs
Publication statusPublished - Mar 13 2020

Keywords

  • CDH-11
  • IBD
  • RhoA/ROCK pathway
  • TGF-β pathway

ASJC Scopus subject areas

  • Gastroenterology

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