Endoplasmic Reticulum Stress in Intestinal Epithelial Cells and Inflammatory Bowel Disease.

Endoplasmic Reticulum Stress;Inflammatory Bowel Disease;Intestinal Epithelial Cells;Biological Chemistry;Health Sciences;Biological Chemistry

Cao, SiyanGumucio, Deborah L. ;

University of Michigan

关键词: Endoplasmic Reticulum Stress;    Inflammatory Bowel Disease;    Intestinal Epithelial Cells;    Biological Chemistry;    Health Sciences;    Biological Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/99965/sycao_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Recent studies linked endoplasmic reticulum stress and the unfolded protein response (UPR) to inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis. My PhD research has been focused on the physiological roles of UPR components in intestinal epithelial cells (IECs) and the pathogenesis of IBD, as well as the therapeutic effects of ER stress-modulating compounds for this disease.Using murine genetic models, I first showed that ER co-chaperone P58IPK/DNAJC3 as well as activating transcription factor 6 alpha (ATF6a), an essential transcriptional activator of ER chaperone genes, are protective against chemical-induced colitis in mice. In response to colonic inflammation, Atf6a-/- and P58IPK-/- mice showed impaired ER chaperone response and a selective activation of pro-apoptotic UPR, suggesting ER chaperones are important for the function and survival of IECs and mucosal homeostasis. Then I tested the therapeutic potential of chemical chaperones 4-phenylbutyrate (PBA) and tauroursodeoxycholate (TUDCA), two bioactive small molecules that facilitate protein folding and trafficking in cells. PBA or TUDCA significantly reduced inflammation-induced ER stress in IECs both in vitro and in vivo. Feeding of PBA or TUDCA dramatically ameliorated the signs of colitis in several murine models. Phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2a-P) regulates global protein synthesis and UPR transcription in response to ER stress. Altered eIF2a-P was observed in mucosal tissue of patients with IBD. To study the mechanistic role of eIF2a-P in IECs, I analyzed mice with conditional expression of non-phosphorylatable Ser51Ala mutant eIF2a in IECs (AAIEC mice). Under normal conditions, the AAIEC mice displayed reduced lysozyme, suggesting a disrupted Paneth cell function. Paneth cell ultrastructure demonstrated a reduced number of secretory granules, increased vesicles, and mitochondrial damage in AAIEC mice. In addition, AA IECs exhibited compromised UPR signaling, ER protein translocation machinary, and autophagy, which may contribute to the protein secretion defects in AA Paneth cells. Consistent to the IEC dysfunction, AAIEC mice were more susceptible to oral infection of Salmonella Typhimurium and chemical-induced colitis. I believe these findings have improved our understainng of IBD pathogenesis and opened a new avenue to IBD therapeutics in the future.