Int J Biol Sci 2023; 19(14):4360-4375. doi:10.7150/ijbs.82302 This issue Cite
Research Paper
1. School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China.
2. Department of Pharmacy, Peking University Shenzhen Hospital, Shenzhen, China.
3. The State Key Laboratory of Functions and Applications of Medicinal Plants and The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, Guizhou, China.
4. Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
5. Department of Gastroenterology, Peking University Shenzhen Hospital, Shenzhen, China.
6. School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong.
*These authors have contributed equally to this work.
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.
Keywords: inflammatory bowel disease, intestinal mucosa repair, P2Y1R, AMPK, gut microbiota