P2RY13 Exacerbates Intestinal Inflammation by Damaging the Intestinal Mucosal Barrier via Activating IL-6/STAT3 Pathway

Abstract

The pathogenesis of ulcerative colitis (UC) is unclear, while genetic factors have been confirmed to play an important role in its development. P2RY13 is a G protein-coupled receptor (GPCRs), which are involved in the pathogenesis of inflammation and immune disorders. According to GEO database analysis, we first observed that the expression of P2Y13 was increased in UC patients. Therefore, we sought to determine the role of P2Y13 in the development of colitis. Our data showed that P2RY13 was highly expressed in the inflamed intestinal tissues of UC patients. In mice, pharmacological antagonism of P2Y13 can significantly attenuate the intestinal mucosal barrier disruption. In LPS-induced NCM460 cell, knockdown or pharmacological inhibition of P2RY13 increased the expression of intestinal tight junction protein and reduced apoptosis. In addition, we found that the effect of P2Y13 on colitis is related to the activation of the IL-6/STAT3 pathway. Activation of P2Y13 increases IL-6 expression and promotes STAT3 phosphorylation and nuclear transport. Deletion of the STAT3 gene in the intestinal epithelial cells of mice significantly mitigated the exacerbation of colitis due to P2Y13 activation. Thus, P2Y13 can aggravate intestinal mucosal barrier destruction by activating the IL-6/STAT3 pathway. P2Y13 might be a potential drug target for UC.

Commensal Enterococcus faecalis W5 ameliorates hyperuricemia and maintains the epithelial barrier in a hyperuricemia mouse model

“…Further analysis showed that E. faecalis UA. Our previous study also found that the bacteria enriched the purine salvage-related proteins could decrease UA, 16 35 and IL-6 can increase the permeability of TJ proteins. For example, IL-6 leads to an approximately 3-4-fold increase in the transepithelial flux of urea.…”

Transcriptomic analysis reveals shared gene signatures and molecular mechanisms between obesity and periodontitis

“…The product of the P2RY13 gene belongs to the G protein-coupled receptor family, a 354 amino acid-encoded gastrointestinal protein-coupled receptor that is involved in the pathogenesis of purine energy transfer pathways, cholesterol metabolism, inflammation and immune dysfunction mechanisms, mediating a variety of pathophysiological processes, such as apoptosis, autophagy, proliferation and metabolism ( 72 , 73 ). Many studies have shown that P2RY13 promotes apoptosis and increases the release of pro-inflammatory factors ( 74 , 75 ). In addition, P2RY13 is highly expressed in the inflamed intestinal tissue of ulcerative colitis patients ( 74 , 76 ).…”

“…Many studies have shown that P2RY13 promotes apoptosis and increases the release of pro-inflammatory factors ( 74 , 75 ). In addition, P2RY13 is highly expressed in the inflamed intestinal tissue of ulcerative colitis patients ( 74 , 76 ). The above series of studies have shown that FGR , LCK , FYB1 , LY86 , and P2RY13 may play an important role in the dysfunction of immune cells such as macrophages, T lymphocytes, and B lymphocytes during the pathology of OB or PD.…”

P2RY13 is a prognostic biomarker and associated with immune infiltrates in renal clear cell carcinoma: A comprehensive bioinformatic study

“…P2RY13 a G protein‐coupled receptor that reacts to extracellular purine and pyrimidine nucleotides, negatively regulates adenylate cyclase activity 13 . Encoded by 354 amino acids (aa), it is linked to the development of inflammation and immune conditions 14 . While P2RY13 is particularly sensitive to ADP, it can be triggered by both ADP and ATP.…”

“…13 Encoded by 354 amino acids (aa), it is linked to the development of inflammation and immune conditions. 14 While P2RY13 is particularly sensitive to ADP, it can be triggered by both ADP and ATP. Research indicates a crucial function of P2RY13 in inflammation and immune imbalance.…”