title: 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.
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Service de Gastroentérologie et d'Assistance Nutritive, PMAD Hôpital Beaujon, Clichy la Garenne, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Tréton
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Pedruzzi
authors.affiliation: Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; INSERM, UMRS871, Centre Biomédical des Cordeliers, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Guichard
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Ladeiro
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Shirin
authors.initials: S
authors.lastname: Sedghi
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Mélissa
authors.initials: M
authors.lastname: Vallée
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Neike
authors.initials: N
authors.lastname: Fernandez
authors.affiliation: INSERM, UMR837, Team 5 «Mucins, epithelial differentiation and carcinogenesis», Jean-Pierre Aubert Research Center, Lille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bruyère
authors.affiliation: Laboratoire de Bacteriologie, Hôpital Bichat-Claude Bernard, Paris, France.
authors.forename: Paul-Louis
authors.initials: PL
authors.lastname: Woerther
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Ducroc
authors.affiliation: INSERM, U989, Université Paris-Descartes, Necker, Paris, France; Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Montcuquet
authors.affiliation: INSERM, U682, Université Louis Pasteur, Strasbourg, France.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Freund
authors.affiliation: INSERM, UMR837, Team 5 «Mucins, epithelial differentiation and carcinogenesis», Jean-Pierre Aubert Research Center, Lille, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
authors.affiliation: Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France; INSERM, U843 Hôpital R. Debré, Paris, France.
authors.forename: Frédérick
authors.initials: F
authors.lastname: Barreau
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Service de Gastroentérologie et d'Assistance Nutritive, PMAD Hôpital Beaujon, Clichy la Garenne, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Assiya
authors.initials: A
authors.lastname: Marah
authors.affiliation: Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France; INSERM, U843 Hôpital R. Debré, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hugot
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France; Service d'Anatomo-Pathologie, Hôpital Beaujon, Clichy, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Cazals-Hatem
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Service de Gastroentérologie et d'Assistance Nutritive, PMAD Hôpital Beaujon, Clichy la Garenne, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Bouhnik
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Daniel
authors.affiliation: INSERM, UMRS1149, Team «Physiopathology of Inflammatory Bowel Diseases», Centre de Recherche sur l'Inflammation, Paris, France; Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; Laboratory of Excellence Labex INFLAMEX, PRES Paris Sorbonne Cité, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Ogier-Denis
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000502:physiology*; D000074624:NADPH Oxidase 1; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056811:Unfolded Protein Response
chemical_list: D012333:RNA, Messenger; D016753:Interleukin-10; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1