Combined NADPH oxidase 1 and interleukin 10 deficiency induces chronic endoplasmic reticulum stress and causes ulcerative colitis-like disease in mice

Xavier Tréton; Eric Pedruzzi; Cécile Guichard; Yannick Ladeiro; Shirin Sedghi; Mélissa Vallée; Neike Fernandez; Emilie Bruyère; Paul-Louis Woerther; Robert Ducroc; Nicolas Montcuquet; Jean-Noel Freund; Isabelle Van Seuningen; Frédérick Barreau; Assiya Marah; Jean-Pierre Hugot; Dominique Cazals-Hatem; Yoram Bouhnik; Fanny Daniel; Eric Ogier-Denis

doi:10.1371/journal.pone.0101669

Combined NADPH oxidase 1 and interleukin 10 deficiency induces chronic endoplasmic reticulum stress and causes ulcerative colitis-like disease in mice

PLoS One. 2014 Jul 9;9(7):e101669. doi: 10.1371/journal.pone.0101669. eCollection 2014.

Authors

Xavier Tréton¹, Eric Pedruzzi², Cécile Guichard³, Yannick Ladeiro², Shirin Sedghi², Mélissa Vallée², Neike Fernandez², Emilie Bruyère⁴, Paul-Louis Woerther⁵, Robert Ducroc², Nicolas Montcuquet⁶, Jean-Noel Freund⁷, Isabelle Van Seuningen⁴, Frédérick Barreau⁸, Assiya Marah¹, Jean-Pierre Hugot⁸, Dominique Cazals-Hatem⁹, Yoram Bouhnik¹, Fanny Daniel², Eric Ogier-Denis²

Affiliations

¹ 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.
² 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.
³ Université Paris-Diderot Sorbonne Paris-Cité, Paris, France; INSERM, UMRS871, Centre Biomédical des Cordeliers, Paris, France.
⁴ INSERM, UMR837, Team 5 «Mucins, epithelial differentiation and carcinogenesis», Jean-Pierre Aubert Research Center, Lille, France.
⁵ Laboratoire de Bacteriologie, Hôpital Bichat-Claude Bernard, Paris, France.
⁶ INSERM, U989, Université Paris-Descartes, Necker, Paris, France; Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France.
⁷ INSERM, U682, Université Louis Pasteur, Strasbourg, France.
⁸ 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.
⁹ 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.

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Case-Control Studies
Cell Proliferation
Cells, Cultured
Colitis, Ulcerative / etiology*
Colitis, Ulcerative / metabolism
Colitis, Ulcerative / pathology
Colon / immunology
Colon / metabolism
Colon / pathology
Disease Models, Animal*
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum / pathology
Endoplasmic Reticulum Stress*
Female
Flow Cytometry
Fluorescent Antibody Technique
Humans
Immunoenzyme Techniques
Inflammation / etiology*
Inflammation / metabolism
Inflammation / pathology
Interleukin-10 / physiology*
Intestinal Mucosa / metabolism
Intestinal Mucosa / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NADH, NADPH Oxidoreductases / physiology*
NADPH Oxidase 1
Phosphorylation
Protein Phosphatase 1 / genetics
Protein Phosphatase 1 / metabolism
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Unfolded Protein Response

Substances

RNA, Messenger
Interleukin-10
NADH, NADPH Oxidoreductases
NADPH Oxidase 1
NOX1 protein, mouse
Ppp1r15a protein, mouse
Protein Phosphatase 1

Grants and funding

This work was supported by grants from: Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM-Transfert (CoPoC’s grant to XT and EOD), Agence Nationale de la Recherche (ANR Emergence to EOD), Association François Aupetit (AFA) (to XT and EOD), Assistance Publique-Hôpitaux de Paris (AP-HP) (to EOD: Interface Fellowship), University Denis Diderot Paris 7, and labex “Inflamex” (to EOD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.