Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the rectum which progressively extents. Its etiology remains unknown and the number of treatments available is limited. Studies of UC patients have identified an unbalanced endoplasmic reticulum (ER) stress in the non-inflamed colonic mucosa. Animal models with impaired ER stress are sensitive to intestinal inflammation, suggesting that an unbalanced ER stress could cause inflammation. However, there are no ER stress-regulating strategies proposed in the management of UC partly because of the lack of relevant preclinical model mimicking the disease. Here we generated the IL10/Nox1dKO mouse model which combines immune dysfunction (IL-10 deficiency) and abnormal epithelium (NADPH oxidase 1 (Nox1) deficiency) and spontaneously develops a UC-like phenotype with similar complications (colorectal cancer) than UC. Our data identified an unanticipated combined role of IL10 and Nox1 in the fine-tuning of ER stress responses in goblet cells. As in humans, the ER stress was unbalanced in mice with decreased eIF2α phosphorylation preceding inflammation. In IL10/Nox1dKO mice, salubrinal preserved eIF2α phosphorylation through inhibition of the regulatory subunit of the protein phosphatase 1 PP1R15A/GADD34 and prevented colitis. Thus, this new experimental model highlighted the central role of epithelial ER stress abnormalities in the development of colitis and defined the defective eIF2α pathway as a key pathophysiological target for UC. Therefore, specific regulators able to restore the defective eIF2α pathway could lead to the molecular remission needed to treat UC.
Highlights
Ulcerative colitis (UC) is the most common chronic inflammatory disorder affecting exclusively the colon [1]
Statistics are as in (A). doi:10.1371/journal.pone.0101669.g005. We showed that both immunological and epithelial deficiencies in mice lacking the anti-inflammatory cytokine IL10 and NADPH oxidase 1 (Nox1) sensitized the colon to spontaneously develop severe colitis and mimicked all clinical and histological characteristics of UC. We showed that both IL10 and NOX1 expression levels were decreased in the non-inflamed colonic mucosa of UC patients compared to healthy controls
We can assume that IL10 and Nox1 could play a central role in UC pathogenesis and cooperate to modulate the unfolded protein response (UPR) and inflammation, in goblet cells
Summary
Ulcerative colitis (UC) is the most common chronic inflammatory disorder affecting exclusively the colon [1]. UC is a complex disease due to deregulated interactions between epithelial cells, immune and environmental factors. A growing body of evidence suggests that the colonic epithelial homeostasis could be a critical element mediating protection from detrimental environmental factors and regulating underlying inflammatory responses in UC [2,3,4,5]. Especially goblet cells whose secretory functions depend on protein synthesis, have developed evolved mechanisms to cope with cellular stresses such as the ER stress and inflammation. It is evident that an unresolved ER stress in intestinal epithelial cells associated with altered unfolded protein response (UPR)
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