Disruption of epithelium integrity by inflammation-associated fibroblasts through prostaglandin signaling.

Autor: Dong Y; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Johnson BA; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Ruan L; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Zeineldin M; Department of Pathology, Division of GI/Liver Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Bi T; Department of Pathology, Division of GI/Liver Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Liu AZ; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Raychaudhuri S; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Chiu I; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Zhu J; Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, Singapore, Singapore., Smith B; Microscope Facility, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Zhao N; Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD 21218, USA., Searson P; Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD 21218, USA.; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD 21218, USA., Watanabe S; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Donowitz M; Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.; Department of Physiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Larman TC; Department of Pathology, Division of GI/Liver Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA., Li R; Department of Cell Biology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.; Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, Singapore, Singapore.; Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Apr 05; Vol. 10 (14), pp. eadj7666. Date of Electronic Publication: 2024 Apr 03.
DOI: 10.1126/sciadv.adj7666
Abstrakt: Inflammation-associated fibroblasts (IAFs) are associated with progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial cells is unknown. Here, we developed an in vitro model whereby human colon fibroblasts are induced by specific cytokines and recapitulate key features of IAFs in vivo. When cocultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid expansion and barrier disruption due to swelling and rupture of individual epithelial cells. Colonoids cocultured with IAFs also show increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated by a paracrine pathway involving prostaglandin E 2 and its receptor EP4, leading to protein kinase A -dependent activation of the cystic fibrosis transmembrane conductance regulator. EP4-specific chemical inhibitors effectively prevented IAF-induced colonoid swelling and restored normal proliferation and genome stability. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a therapeutic avenue to mitigate inflammation-associated epithelial injury.
Databáze: MEDLINE
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