Epithelial Gasdermin D shapes the host-microbial interface by driving mucus layer formation

Area of Science:

• Gastroenterology
• Cell Biology
• Immunology

Background:

• Goblet cells and mucus are vital for colonic homeostasis and host-microbe interactions.
• The intracellular mechanisms governing mucus secretion are not fully understood.
• Gasdermin D (GSDMD) is known for its role in pyroptosis, a pro-inflammatory cell death.

Purpose of the Study:

• To investigate the role of GSDMD in goblet cell mucin secretion and mucus layer formation.
• To elucidate the molecular mechanisms by which GSDMD influences mucus secretion.
• To determine the physiological significance of GSDMD in maintaining gut mucosal homeostasis.

Main Methods:

• Specific deletion of GSDMD in intestinal epithelial cells (ΔIEC) in mice.
• Assessment of mucus secretion and mucus layer integrity.
• Analysis of host-microbial interactions and pathogen clearance.
• Investigation of the molecular pathways involving caspases, reactive oxygen species, and scinderin.

Main Results:

• Deletion of GSDMD abrogated mucus secretion and led to mucus layer loss.
• GSDMD-deficient mice exhibited a disturbed host-microbial interface and impaired pathogen clearance.
• GSDMD activation, via caspases and ROS, triggers calcium-dependent scinderin-mediated F-actin disassembly, promoting mucin secretion.
• This process represents a non-pyroptotic function of GSDMD in the secretory granule exocytotic pathway.

Conclusions:

• Epithelial GSDMD plays a critical, non-pyroptotic role in regulating goblet cell mucin secretion.
• GSDMD is essential for maintaining the colonic mucus layer and gut mucosal homeostasis.
• This finding links GSDMD to the physiological regulation of secretory granule exocytosis in the gut.