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P003. Selective inhibition of eIF2alpha dephosphorylation prevents colitis and shows therapeutic potential in a new model of ulcerative colitis

X. Treton1, E. Pedruzzi1, C. Guichard2, M. Vallee1, S. Sedghi1, Y. Ladeiro1, N. Montcuquet3, J.N. Freund4, I. Van Seuningen5, F. Barreau1, J.P. Hugot1, D. Cazals-Hatem6, F. Daniel1, E. OgierDenis1, Y. Bouhnik7, 1Paris 7 University, Inserm U773, Paris, 2Univ. Paris-Diderot Sorbonne Paris-Cité, INSERM U674, 3Univ. Paris-Diderot Sorbonne Paris-Cité, INSERM U989, 4Inserm U 682, Strasbourg, 5INSERM UMR837, Lille, 6Hôpital Beaujon, APHP, Pathology, Clichy, 7Hôpital Beaujon, APHP, Gastroenterology, Clichy, France

Background

Endoplasmic reticulum stress (ERS) is disturbed in the uninflamed colonic mucosa. In particular, characteristic eIF2 hypo-phosphorylation, which may preclude inflammatory damage. No treatment strategies to regulate ERS exist today. We hypothesized that pharmacological restoration of eIF2 phosphorylation may become a new therapeutic approach.

Methods

We made C157-BL6 mice invalidated for NADPH-Oxidase 1 (NOX1) and interleukin 10 (IL-10). These double NOX1/IL-10 knock-out (KO) mice (EXCY2) were compared to three control groups: wild type (WT), NOX1-KO and IL-10-KO, age matched and reared with controlled pathogen-free animal husbandry. 35 EXCY2 mice were followed to 8 months old to study the long term outcome of colitis. Clinical disease activity index, histological, immunological and biochemical parameters of colon and liver were analyzed in all groups at 3, 4, 6 and 8 weeks old. The preventive effect of Salubrinal, known to restore eIF2 phosphorylation, was studied. 15 EXCY2 received intraperitoneal injections of salubrinal (1 mg/kg/72 hrs) and 10 EXCY2 a vector, from week 3 to week 6.

Results

All EXCY2 mice (n = 150) spontaneously developed colitis at 6/7 weeks old. Colitis features accurately imitated the entire human UC phenotype. i.e. anatomical (lesions progressing upstream from the distal colon), histological (ulcerations, loss of mucosecretion, crypt abscesses and neutrophilic infiltration) and immunological (increase cytokines TNF, IL-17A, IL-13 CD4+ T lymphocytes in the lamina propria). The colonic epithelium expressed eIF2 hypo-phosphorylation before onset of colitis (in 3 to 4 week-old EXCY2). Long-term follow-up showed: a) high-grade dysplasia or invasive colon cancer in 40% of cases. b) typical sclerosing cholangitis lesions in 25% of cases. Salubrinal restored colonic ER stress homeostasis by reestablishing eIF2 α phosphorylation. Colitis onset was prevented in all treated mice and in none of the control group (p < 0.001).

Conclusion

EXCY2 is a murine model that develops spontaneous UC-like phenotype including complications such as colorectal cancer and primary sclerosing cholangitis. It expresses disturbed ERS with decreased eIF2phosphorylation before inflammation. Specific regulators of eIF2 pathways may be a promising therapy. EXCY2 should is a suitable colitis model to evaluate drug efficacy at preclinical level. Mechanistic studies to understand the effects of environmental factors, such as tobacco and appendicitis can be performed with EXCY2.