Tréton Xavier, Pedruzzi Eric, Guichard Cécile, Ladeiro Yannick, Sedghi Shirin, Vallée Mélissa, Fernandez Neike, Bruyère Emilie, Woerther Paul-Louis, Ducroc Robert, Montcuquet Nicolas, Freund Jean-Noel, Van Seuningen Isabelle, Barreau Frédérick, Marah Assiya, Hugot Jean-Pierre, Cazals-Hatem Dominique, Bouhnik Yoram, Daniel Fanny, Ogier-Denis Eric
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.
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.
PLoS One. 2014 Jul 9;9(7):e101669. doi: 10.1371/journal.pone.0101669. eCollection 2014.
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.
溃疡性结肠炎（UC）是一种慢性炎症性肠病，累及直肠并逐渐蔓延。其病因尚不清楚，可用的治疗方法数量有限。对UC患者的研究发现，在未发炎的结肠黏膜中存在内质网（ER）应激失衡。内质网应激受损的动物模型对肠道炎症敏感，这表明内质网应激失衡可能导致炎症。然而，在UC的治疗中尚未提出内质网应激调节策略，部分原因是缺乏模拟该疾病的相关临床前模型。在此，我们构建了IL10/Nox1双敲除小鼠模型，该模型结合了免疫功能障碍（IL-10缺陷）和上皮异常（NADPH氧化酶1（Nox1）缺陷），并自发发展出与UC相似的表型及并发症（结直肠癌）。我们的数据确定了IL10和Nox1在杯状细胞内质网应激反应微调中的意外联合作用。与人类一样，在炎症发生前eIF2α磷酸化降低的小鼠中内质网应激失衡。在IL10/Nox1双敲除小鼠中，salubrinal通过抑制蛋白磷酸酶1的调节亚基PP1R15A/GADD34来维持eIF2α磷酸化，并预防结肠炎。因此，这个新的实验模型突出了上皮内质网应激异常在结肠炎发展中的核心作用，并将有缺陷的eIF2α途径定义为UC的关键病理生理靶点。因此，能够恢复有缺陷的eIF2α途径的特异性调节剂可能会带来治疗UC所需的分子缓解。
