The Endoplasmic Reticulum Stress Sensor IRE1α in Intestinal Epithelial Cells Is Essential for Protecting against Colitis.
Intestinal epithelial cells (IECs) have critical roles in maintaining homeostasis of intestinal epithelium. Endoplasmic reticulum (ER) stress is implicated in intestinal epithelium homeostasis and inflammatory bowel disease; however, it remains elusive whether IRE1α, a major sensor of ER stress, is directly involved in these processes. We demonstrate here that genetic ablation of Ire1α in IECs leads to spontaneous colitis in mice. Deletion of IRE1α in IECs results in loss of goblet cells and failure of intestinal epithelial barrier function. IRE1α deficiency induces cell apoptosis through induction of CHOP, the pro-apoptotic protein, and sensitizes cells to lipopolysaccharide, an endotoxin from bacteria. IRE1α deficiency confers upon mice higher susceptibility to chemical-induced colitis. These results suggest that IRE1α functions to maintain the intestinal epithelial homeostasis and plays an important role in defending against inflammation bowel diseases.
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Hai-Sheng
HS
Zhang
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Ying
Y
Chen
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Li
L
Fan
the Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030.
Qiu-Lei
QL
Xi
the Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030.
Guo-Hao
GH
Wu
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Xiu-Xiu
XX
Li
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Tang-Long
TL
Yuan
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Sheng-Qi
SQ
He
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Yue
Y
Yu
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Meng-Le
ML
Shao
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031.
Yang
Y
Liu
the Department of Pathology, Changhai Hospital, the Second Military Medical University, Shanghai 200433.
Chen-Guang
CG
Bai
the Department of Pathology, Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital and Zhejiang Cancer Center, Hangzhou 310022.
Zhi-Qiang
ZQ
Ling
the Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
Min
M
Li
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, liuy@sibs.ac.cn.
Yong
Y
Liu
From the Laboratory of Food Safety Research, Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, the Department of Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200030, the Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, and jfang@sibs.ac.cn.
Jing
J
Fang
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003092:Colitis / Q000517:prevention & control*; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics
D017931:DNA Primers; D034741:RNA, Small Interfering; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
colitis; endoplasmic reticulum stress (ER stress); inflammation; inflammatory bowel disease (IBD); intestinal epithelium