Resistance to apoptosis in complicated Crohn's disease: Relevance in ileal fibrosis

Autors de IIS La Fe

• Marta Seco Cervera

  Autor

• Jesús Cosín Roger

  Autor

• Francisco Navarro Vicente

  Autor

• Mónica Millán Scheiding

  Autor

Autors aliens a IIS La Fe

• Ortiz-Masiá D
• Macias-Ceja DC
• Coll S
• Gisbert-Ferrándiz L
• Bauset C
• Ortega M
• Heras-Morán B
• Esplugues JV
• Calatayud S
• Barrachina MD

Grups d'Investigació

• Cirugía digestiva y Cuidados perioperatorios

  

  Leader

  Matteo Frasson

Abstract

Background and aims: The stiffening of the extracellular matrix, and changes in its cellular and molecular composition, have been reported in the pathogenesis of fibrosis. We analyze the mechanisms that perpetuate ileal fibrosis in surgical resections of complicated Crohn's disease patients.Methods: Ileal resections were obtained from affected and non-affected tissue of stenotic or penetrating Crohn's disease behavior. Ilea from non-IBD patients were used as control tissue. All samples underwent RNA sequencing. Human small intestinal fibroblasts were treated for 48 h with IL-1 beta, TFG beta 1, PDGFB or TNF-alpha. Resistance to apoptosis was analysed by RT-PCR, western blot and immunohistochemistry in ileal tissue and by RT-PCR and FACS in cultured cells.Results: Growth factor-driven signaling pathways and increased RAS GTPase activity were up-regulated in affected ilea in which we found expression of both the antiapoptotic molecule MCL1 and the transcription factor ETS1 in submucosal fibroblasts, and a senescence-associated secretory phenotype. In cultured intestinal fibro-blasts, PDGFB induced an ETS1-mediated resistance to apoptosis that was associated with the induction of both of TGFB1 and IL1B, a cytokine that replicated the expression of SASP detected in ileal tissue. ETS1 drove fibroblast polarization between inflammatory and fibrogenic phenotypes in IL1 beta-treated cells. Conclusions: Our data show resistance to apoptosis in complicated ileal CD, and demonstrate that PDGFB induce an ETS1-mediated resistance to apoptosis associated with an inflammatory and fibrogenic pattern of expression in intestinal fibroblasts. Results point to PDGFRB, IL1R1 or MCL1 as potential targets against ileal fibrosis.

Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Keywords

• Fibrosis; Crohn's disease; Fibroblasts; Apoptosis; Senescence -associated secretory phenotype