STING activation promotes intestinal mucin secretion in IBD.

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• Goblet cells and mucus protect the intestinal lining.
• Inflammatory bowel diseases (IBD) are linked to goblet cell loss and mucus layer disruption.
• The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway's role in goblet cell depletion is complex, with both deficiency and overactivation causing issues.

Purpose of the Study:

• To investigate the role of the cGAS-STING pathway in regulating goblet cell mucus production in IBD patients.
• To analyze STING pathway activation and MUC2 expression in human colonic organoids (HCO).

Main Methods:

• Analyzed MUC and cGAS-STING gene expression in IBD patient mucosa (n=821) and controls.
• Performed MUC2 and STING pathway immunohistochemistry.
• Treated human colonic organoids (HCO) with STING agonist (diABZI) and antagonist (H151).
• Assessed STING activation and MUC2 regulation using qPCR, Western blotting, and immunofluorescence microscopy.

Main Results:

• Inflamed IBD mucosa showed increased MUC and cGAS-STING pathway gene expression.
• Reduced mucus-filled goblet cells were observed in inflamed IBD mucosa, despite increased immature MUC2 and activated STING.
• STING activation in HCO led to increased mature MUC2 accumulation and reduced mucus-filled goblet cells.
• STING antagonism did not decrease mucus-filled goblet cells in HCO.

Conclusions:

• STING pathway activation promotes excessive mucus release in inflamed IBD epithelium.
• This enhanced mucus release provides a mechanistic explanation for the observed histological depletion of goblet cells in IBD.