The expression of P2Y₆ receptor promotes the quality of mucus in colitic mice

Abstract

In the intestine, mucins are expressed and secreted by goblet cells and enterocytes in a constitutive manner and in response to secretagogues to form a protective mucus layer. This protective barrier is often lost in inflammatory bowel disease (IBD). Interestingly, extracellular nucleotides, through P2Y receptors, were identified as mucin secretagogues in mucinous epithelia. These nucleotides are found in the intestine’s extracellular milieu under basal conditions and in higher concentrations in pathologies such as IBD. It was observed that the mucus layer was affected in P2ry6 knockout mice suffering from dextran sodium sulfate (DSS)‐induced colitis. P2ry6−/− mice were more sensitive to DSS‐induced colitis, resulting in larger ulcers and increased disease activity index. Interestingly, the absence of P2Y6 receptor expression negatively affected the mucus quality, as shown by a reduction in sulfomucin staining and the absence of a dense internal fucosylated mucin layer in P2ry6−/− mice. Hence, we cannot rule out that the absence of P2Y6 receptors in knockout animals could negatively impact mucin secretion. However, we did not measure a reduction in the number of goblet cells, as previously reported. Instead, the results suggest that goblet cells rapidly discharged mucins to compensate for the mucus layer's increased lability, which resulted in empty goblet cells that are less visible to mucin staining. This study's results, along with previous reports, point toward a protective role for the P2Y6 receptor in IBD.

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

“…Increasing evidence show that P2Y receptor is involved in the pathogenesis of inflammatory diseases and tumors 14 . While the P2Y1, P2Y2 and P2Y6 of P2Y receptor involved in the development of UC has been described 12 , 26 - 27 , the role of P2RY13 in UC has never been investigated. P2RY13 is one of the important members of the P2Y receptor family and is synthesized by 354 amino acid codes.…”

Exploration of the link between gut microbiota and purinergic signalling

“…It has also been found that ENTPDase8 can similarly reduce intestinal inflammation by limiting P2Y6 receptor activation [ 36 ]. But additional studies on the P2Y6 receptor have found that P2Y6 − / − mice are more susceptible to DSS-induced inflammation than WT mice, and P2Y6 deficiency can affect the secretion of a protective mucus layer in the gut or lead to abnormal activation of Th17/Th1 lymphocytes [ 37 , 38 ]. This change may be related to the alteration of intestinal microbiota after P2 receptor deletion, and high-affinity IgA may maintain the balance of intestinal ecology by limiting the growth of certain bacteria.…”

P2X4 receptor modulates gut inflammation and favours microbial homeostasis in colitis

“…Mice lacking P2ry6 are more susceptible to colitis induced by dextran sodium sulphate (DSS) via ulcer promotion, suggesting a protective role in IBD. 12 …”

“…The P2 receptor family is widely distributed and expressed in the enteric nervous system and epithelial cells, suggesting that it has a key role in IBD pathogenesis. Mice lacking P2ry6 are more susceptible to colitis induced by dextran sodium sulphate (DSS) via ulcer promotion, suggesting a protective role in IBD 12 …”

“…Mice lacking P2ry6 are more susceptible to colitis induced by dextran sodium sulphate (DSS) via ulcer promotion, suggesting a protective role in IBD. 12 Furthermore, P2X7 receptor expression varies in the mucosa of patients with active and quiescent IBD. Its inactivation may impair inflammatory response but increase tumor incidence in DSS-induced colitis-associated cancer, as it is involved in the processing and release of interleukin (IL)-1β.…”