Open Collections

UBC Theses and Dissertations

UBC Theses Logo
Featured Collection

UBC Theses and Dissertations

Inflammasome signalling and its impact on intestinal mucosal defense Han, Xiao (Vivian)

Abstract

This thesis explores the intricate dynamics of inflammasome activation in human and murine intestinal epithelial cells (IECs) as well as its role in the mucus secretion that ensues during enteric Salmonella enterica Typhimurium infection. Using in vitro organoid cultures derived from human and mouse ileum, we observed distinct differences in inflammasome activation between human and murine IECs. Through knockout experiments targeting pro-inflammatory caspases in human and murine organoids, we discovered that human IECs rely on non-canonical inflammasome activation through caspase-4, whereas murine IECs primarily depend on canonical inflammasome activation through caspase-1 to curb cytosolic S. Typhimurium replication and promote interleukin (IL)-18 production. These findings shed light on species-specific variations in inflammasome signaling pathways and their response to invading pathogenic microbes. In vivo experiments using mouse models investigated the effects of inflammasome activation on the intestinal epithelium, and specifically goblet cells and mucin secretion. We observed that inflammasome activation modulates goblet cell function in the cecum and distal colon, promoting mucin secretion in response to S. Typhimurium infection. Deficiencies in caspase-1 and caspase-11 resulted in reduced mucin secretion, as indicated by thinner mucus layers in the distal colon. The cytokines IL-18 and IL-22 were found to play crucial roles in stimulating cecal mucin secretion, with IL-22 regulating IL-18 production. Supplementation of recombinant IL-18 rescued the reduced mucin secretion in IL-22-deficient mice. Additionally, NLRP6 inflammasomes were found to be modestly involved in modulating mucin secretion in the distal colon, albeit through IL-22- and IL-18-independent pathways. These findings underscore the complex interactions between inflammasome activation, cytokines, and mucin secretion in the intestinal epithelium during S. Typhimurium infection. The observed differences in inflammasome activation between human and murine IECs emphasize the importance of considering species-specific differences when translating research findings to clinical applications. The correlation between mucin secretion and inflammasome signaling provides valuable insights into the mechanisms underlying host defense against S. Typhimurium by curbing bacterial colonization and dissemination. Moreover, these findings may ultimately aid in the development of targeted therapeutic strategies for combating enteric pathogens and associated gastrointestinal disorders.

Item Metadata

Title
Inflammasome signalling and its impact on intestinal mucosal defense
Creator
Han, Xiao (Vivian)
Supervisor
Vallance, Bruce A.
Publisher
University of British Columbia
Date Issued
2023
Description
This thesis explores the intricate dynamics of inflammasome activation in human and murine intestinal epithelial cells (IECs) as well as its role in the mucus secretion that ensues during enteric Salmonella enterica Typhimurium infection. Using in vitro organoid cultures derived from human and mouse ileum, we observed distinct differences in inflammasome activation between human and murine IECs. Through knockout experiments targeting pro-inflammatory caspases in human and murine organoids, we discovered that human IECs rely on non-canonical inflammasome activation through caspase-4, whereas murine IECs primarily depend on canonical inflammasome activation through caspase-1 to curb cytosolic S. Typhimurium replication and promote interleukin (IL)-18 production. These findings shed light on species-specific variations in inflammasome signaling pathways and their response to invading pathogenic microbes. In vivo experiments using mouse models investigated the effects of inflammasome activation on the intestinal epithelium, and specifically goblet cells and mucin secretion. We observed that inflammasome activation modulates goblet cell function in the cecum and distal colon, promoting mucin secretion in response to S. Typhimurium infection. Deficiencies in caspase-1 and caspase-11 resulted in reduced mucin secretion, as indicated by thinner mucus layers in the distal colon. The cytokines IL-18 and IL-22 were found to play crucial roles in stimulating cecal mucin secretion, with IL-22 regulating IL-18 production. Supplementation of recombinant IL-18 rescued the reduced mucin secretion in IL-22-deficient mice. Additionally, NLRP6 inflammasomes were found to be modestly involved in modulating mucin secretion in the distal colon, albeit through IL-22- and IL-18-independent pathways. These findings underscore the complex interactions between inflammasome activation, cytokines, and mucin secretion in the intestinal epithelium during S. Typhimurium infection. The observed differences in inflammasome activation between human and murine IECs emphasize the importance of considering species-specific differences when translating research findings to clinical applications. The correlation between mucin secretion and inflammasome signaling provides valuable insights into the mechanisms underlying host defense against S. Typhimurium by curbing bacterial colonization and dissemination. Moreover, these findings may ultimately aid in the development of targeted therapeutic strategies for combating enteric pathogens and associated gastrointestinal disorders.
Genre
Thesis/Dissertation
Type
Text
Language
eng
Date Available
2023-09-21
Provider
Vancouver : University of British Columbia Library
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
DOI
10.14288/1.0435945
URI
http://hdl.handle.net/2429/85981
Degree
Doctor of Philosophy - PhD
Program
Experimental Medicine
Affiliation
Medicine, Faculty of; Medicine, Department of
Degree Grantor
University of British Columbia
Graduation Date
2023-11
Campus
UBCV
Scholarly Level
Graduate
Rights URI
http://creativecommons.org/licenses/by-nc-nd/4.0/
Aggregated Source Repository
DSpace

Item Media

Loading media...

Item Citations and Data

Permanent URL (DOI):
Rights

Attribution-NonCommercial-NoDerivatives 4.0 International