Inflammasomes in the Intestinal Epithelium

Inflammasomes are multiprotein signalling complexes that detect a diverse range of pathological stimuli to activate inflammatory caspases, resulting in cell death and the release of IL-18 and IL-1. Inflammasomes are important in a wide range of diseases, in particular with auto-inflammatory disorders in humans. While they have been extensively studied in immune cells, their role in mediating inflammatory responses in other cellular compartments is ill-defined. It is becoming increasingly clear that epithelial inflammasomes are critical for controlling intestinal pathogens and regulating epithelial-mucosal homeostasis, little is known about how they function in this cellular compartment. Moreover, very few studies focus specifically on inflammasomes in human cells, and this has implications for our understanding of human diseases. In this thesis we investigate human intestinal epithelial inflammasomes in the two contexts that they are known to function: controlling epithelial-mucosal homeostasis and defending against cytosolic pathogens. We have uncovered that NLRP6 may function to regulate intestinal mucus homeostasis and that disruption of this may underpin the diseases of the microbiota-gut-brain axis. Secondly, we have uncovered the importance of the non-canonical inflammasome and caspase-4 in producing intestinal IL-18. Through this we have discovered a novel mechanism of GSDMD and propose that GSDMD regulates the activity of caspases in the intestinal epithelium. Together these data expand upon the knowledge of innate immune signalling in the human intestinal epithelium, enhancing our understanding of how inflammasomes contribute to defense against pathogens and regulation of the intestinal microenvironment.

Department dc:contributor.department

Immunology

Year dc:date.issued

2023

Author dc:creator

• Bruce, Jessica

Advisors dc:contributor.advisor

• Girardin, Stephen E
• Philpott, Dana J

Handle dc:identifier.uri

http://hdl.handle.net/1807/128251

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/128251