Activation of P2Y1R impedes intestinal mucosa repair during colitis

Qiuchan Huan, Jiao Peng, Yaoyao Chang, Qiansheng Zhang, Tianhang Xing, Danling Jiang, Wenke Chen, Xiangchun Shen, Zhaoxiang Bian, Haitao Xiao*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

2 Citations (Scopus)

Abstract

Delayed intestinal mucosal healing is one of the pathogenic bases for the recurrence of inflammatory bowel disease (IBD), but how the IBD inflammatory environment impedes intestinal mucosa repair remains unclear. Adenosine diphosphate (ADP) is an endogenous ligand of P2Y1R that is highly produced at sites of inflammation. We herein identify a novel role of ADP to directly facilitate inflammation-induced epithelial permeability, delay wound healing, and disrupt tight junction integrity, and we found that P2Y1R, a receptor preferentially activated by ADP, was significantly upregulated in the colonic mucosa of ulcerative colitis (UC) patients and in colonic epithelial cells of colitis mice. Inhibition of P2Y1R significantly increased the epithelial permeability, decreased the wound healing capacity, and impaired the tight junction integrity in TNF-α-challenged Caco-2 cells. In parallel, the same effects in promoting intestinal mucosa repair were observed in DSS-induced colitis in P2Y1R-/- mice. Mechanistic investigation revealed that P2Y1R inhibition facilitated epithelial AMP-activated protein kinase (AMPK) phosphorylation and gut microbiota homeostasis reconstruction. Taken together, these findings highlight that P2Y1R activation plays an important role in impeding intestinal mucosa repair during colitis, and that P2Y1R is an attractive target for the therapy of IBD.

Original languageEnglish
Pages (from-to)4360-4375
Number of pages16
JournalInternational Journal of Biological Sciences
Volume19
Issue number14
DOIs
Publication statusPublished - Sept 2023

Scopus Subject Areas

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

User-Defined Keywords

  • gut microbiota
  • inflammatory bowel disease
  • intestinal mucosa repair
  • P2Y1R
  • AMPK

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