Colitis Linked to Endoplasmic Reticulum Stress Induces Trypsin Activity Affecting Epithelial Functions

Area of Science:

• Gastroenterology
• Cell Biology
• Immunology

Background:

• Intestinal epithelial cells (IECs) in inflammatory bowel disease (IBD) show increased endoplasmic reticulum (ER) stress, linked to barrier dysfunction and inflammation.
• IBD colonic tissues and contents have elevated serine protease activity, but the connection to ER stress is unclear.

Purpose of the Study:

• To investigate the association between ER stress and serine protease activity in enterocytes.
• To determine the impact of this association on intestinal barrier function and inflammatory processes.

Main Methods:

• Studied ER stress impact on serine protease secretion in human intestinal cell lines and organoids using Thapsigargin.
• Investigated ER stress-induced proteolytic mechanisms and their effects on IEC biology using protease-activated receptor antagonists.

Main Results:

• IBD patient biopsies showed increased epithelial trypsin-like activity alongside elevated ER stress.
• ER stress induction in human IECs enhanced apical trypsin-like activity, increasing permeability and controlling inflammatory mediators like CXCL8.
• ER stress-associated trypsin activity's detrimental effects were mediated by protease-activated receptors 2 and 4.

Conclusions:

• Excessive ER stress in IECs leads to increased trypsin release.
• This elevated trypsin activity disrupts intestinal barrier function and promotes inflammation.