COX-1/PGE2/EP4 alleviates mucosal injury by upregulating β-arr1-mediated Akt signaling in colitis

Abstract

COX-1/PGE2 is an important protective mediator in ulcerative colitis (UC). β-arrestin1 (β-arr1), which acts as a scaffold protein, is involved in PGE2-mediated signaling pathways. However, the interaction between PGE2 and β-arr1 in maintaining mucosal barrier integrity remains unexplored. In this study, we demonstrated that COX-1 and PGE2 were significantly decreased, and EP4 mRNA was downregulated in both UC patients and mice during the injury phase. PGE2 treatment was found to alleviate mucosal injury and induce EP4 expression during dextran sulfate sodium (DSS)-induced colitis in wild-type (WT) mice. Following DSS-induced injury, β-arr1 deficient mice showed increased signs of colitis compared to β-arr1 WT mice, and the expression of PI3K and p-Akt were remarkably downregulated in β-arr1 deficient mice. In parallel, HCT116 cells transfected with β-arr1 siRNA were examined in the presence or absence of PGE2 in vitro. PGE2 treatment in the β-arr1 WT/KO DSS model and β-arr1 siRNA transfection of HCT116 cells confirmed that PGE2 upregulated β-arr1 in vivo and in vitro. Collectively, our results indicate that COX-1/PGE2/EP4 upregulates the β-arr1 mediated Akt signaling pathway to provide mucosal protection in colitis. Thus, these findings provide support for the future development and clinical application of COX-1/PGE2 in UC.

Dihydroartemisinin Protects against Dextran Sulfate Sodium-Induced Colitis in Mice through Inhibiting the PI3K/AKT and NF-κB Signaling Pathways

“…UC is characterized by inflammation, homeostasis disruption, and epithelial barrier damage in the intestinal tract, and DSS is a well-established agent to induce experimental colitis that is phenotypically similar to UC in humans [29]. DSS-induced colitis is of reasonable reproducibility and of great value for investigating the efficacy of anticolitis agents.…”

E prostanoid receptor 4 expressing macrophages promote the regeneration of the intestinal epithelial barrier upon inflammation

“…However, there is conflicting evidence regarding the level of PGE2 during intestinal inflammation. Peng et al showed that PGE2 was significantly decreased in the colon of patients with UC, as well as in DSS colitis (34), while Maseda et al…”

“…Therefore, our study revealed an essential role of EP4 in the differentiation of wound healing macrophages in the intestine, which 20 can be targeted as a new treatment strategy for IBD. Future work on the expression of EP4 and CD206 in macrophages based on the genetic information together with tracking long-term 34 therapeutic responses might provide further valuable information to develop patient specific therapeutic options.…”

mPGES-1-Mediated Production of PGE2 and EP4 Receptor Sensing Regulate T Cell Colonic Inflammation

“…However, the role of mPGES-1 during intestinal inflammation has not been as deeply studied. mPGES-1-deficient animals are partially protected from dextran sulfate sodium (DSS)-induced colitis (35), and PGE 2 treatment alleviates mucosal injury and induces EP4 expression during DSS-induced colitis in WT mice (39). These data suggest a protective role of mPGES-1-derived PGE 2 during intestinal injuries, but the mechanisms describing how mPGES-1 competence on tissue damaging cells like lymphocytes affects colitis is unknown.…”