Abstract
Colonic epithelial cells comprise the mucosal barrier, and their dysfunction promotes microbial invasion from the gut lumen and induces the development of intestinal inflammation. The EP4 receptor is known to mediate the protective effect of prostaglandin (PG) E2 in the gastrointestinal tract; however, the exact role of epithelial EP4 in intestinal pathophysiology remains unknown. In the present study, we aimed to investigate the role of epithelial EP4 in maintaining colonic homeostasis by characterizing the intestinal epithelial cell-specific EP4 knockout (EP4 cKO) mice. Mice harboring the epithelial EP4 deletion showed significantly lower colonic crypt depth and lower numbers of secretory cell lineages, as well as impaired epithelial cells in the colon. Interestingly, EP4-deficient colon epithelia showed a higher number of apoptotic cells. Consistent with the defect in mucosal barrier function of colonic epithelia and secretory cell lineages, EP4 cKO colon stroma showed enhanced immune cell infiltration, which was accompanied by increased production of inflammatory cytokines. Furthermore, EP4-deficient colons were susceptible to dextran sulfate sodium (DSS)-induced colitis. Our study is the first to demonstrate that epithelial EP4 loss resulted in potential “inflammatory” status under physiological conditions. These findings provided insights into the crucial role of epithelial PGE2/EP4 axis in maintaining intestinal homeostasis.
Highlights
Colonic epithelial cells comprise the mucosal barrier, and their dysfunction promotes microbial invasion from the gut lumen and induces the development of intestinal inflammation
Colonic epithelia were isolated from EP4 knockout (EP4 cKO) mice, and EP4 deletion was confirmed by qRTPCR (Fig. 1B,C)
Our current findings demonstrated that intestinal epithelium-specific EP4 deletion led to a skewed crypt architecture and increased apoptosis of colonic epithelial cells, leading to a potential inflammatory phenotype that is associated with higher susceptibility to experimental colitis
Summary
Colonic epithelial cells comprise the mucosal barrier, and their dysfunction promotes microbial invasion from the gut lumen and induces the development of intestinal inflammation. We aimed to investigate the role of epithelial EP4 in maintaining colonic homeostasis by characterizing the intestinal epithelial cell-specific EP4 knockout (EP4 cKO) mice. Our study is the first to demonstrate that epithelial EP4 loss resulted in potential “inflammatory” status under physiological conditions. These findings provided insights into the crucial role of epithelial PGE2/EP4 axis in maintaining intestinal homeostasis. While PGE2/EP4 signaling is known to affect many cell types, including both epithelial and stromal cells, to regulate the immune system in a pleiotropic manner, these previous studies have not clarified the role of epithelial cell-specific function of EP4 for the maintenance of colonic homeostasis under physiological conditions. EP4 leads to alterations in intestinal crypt architecture and causes the inflammatory phenotype under both physiological and pathological conditions
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