Combined NADPH Oxidase 1 and Interleukin 10 Deficiency Induces Chronic Endoplasmic Reticulum Stress and Causes Ulcerative Colitis-Like Disease in Mice

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.

Nox/Duox Family of NADPH Oxidases: Lessons from Knockout Mouse Models

“…When these mice were crossed with Nox1 knockout animals, the severity of the colitis was reduced, thus proving a role for Nox1-derived ROS in the inflammatory process [18]. In contrast to this finding, the absence of Nox1 in IL-10-deficient animals induced intestinal inflammation, which is probably caused by endoplasmic reticulum stress, developing in double knockout goblet cells [19].…”

ROS in gastrointestinal inflammation: Rescue Or Sabotage?

“…Experimentally, ROS produced by Nox1 during colitis has been studied using Il10 − / − mice as background, as Nox1 deficiency alone did not produce a colitis phenotype in DSS or TNBS models (Leoni et al , ; Treton et al , ). IL‐10 negatively regulates Nox1‐derived ROS production after barrier insult (Li et al , ) as well as following TNF‐α (Kuwano et al , ; Kamizato et al , ), IFN‐γ (Kuwano et al , ; Kamizato et al , ) and LPS (O'Leary et al , ) stimulation.…”

“…IL‐10 negatively regulates Nox1‐derived ROS production after barrier insult (Li et al , ) as well as following TNF‐α (Kuwano et al , ; Kamizato et al , ), IFN‐γ (Kuwano et al , ; Kamizato et al , ) and LPS (O'Leary et al , ) stimulation. When Nox1 − / − mice were crossed with Il10 − / − mice, spontaneous colitis developed mimicking clinical and histological features of UC patients (Treton et al , ). Consistent with findings that Nox1 regulates the balance between goblet and absorptive cell types in the murine colon (Coant et al , ), Nox1 − / − / Il10 − / − mice displayed reduced and aberrant goblet cells and decreased Muc2 and Muc4 mucin expression in ulcerated sites of the intestine (Treton et al , ).…”

Properdin Regulation of Complement Activation Affects Colitis in Interleukin 10 Gene–Deficient Mice

“…One example is deficiency of NADPH oxidase, an enzyme central to the generation of antimicrobial oxygen radicals, leading to exacerbated colitis when combined with IL-10 deficiency. 44 In the absence of neutrophils, extensive interactions between the intestinal epithelium and gut microbes occur, leading to exaggerated proinflammatory responses, ultimately contributing to colonic injury and bacterial translocation to extraintestinal organs. 33 In properdindeficient inflamed mice, impaired neutrophil recruitment was similarly associated with increased colonic bacterial load, higher mucosal expression of harmful cytokines including TNF and IFN-g, and heightened bacterial dissemination.…”