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Author Dhar, Poshmaal.

Title Mucin 1 regulation of the NLRP3 inflammasome

Published 2017

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 UniM INTERNET Thesis    AVAILABLE
Physical description 1 online resource
Thesis notes Thesis (PhD thesis)-- University of Melbourne, Veterinary Science 2017
Summary Mucin 1 (MUC1) is a cell membrane associated, heavily glycosylated protein, widely expressed on mucosal epithelial cells lining the respiratory, gastrointestinal and urogenital tracts of the human body and on immune cells. MUC1 performs multiple functions on epithelial surfaces that confer protection against bacterial pathogens. It can limit the access of pathogens to the host epithelium both by steric hindrance and by acting as a releasable decoy. Additionally, MUC1 functions as a negative regulator of Toll-like receptor signalling pathways, suppressing the downstream production of pro-inflammatory cytokines, thereby reducing inflammation induced by pathogens and their products. While these functions of MUC1 on the epithelial surface have been fairly well investigated, its role on immune cells, and specifically on macrophages, is comparatively unexplored. Infection with the gastric pathogen, Helicobacter pylori is the underlying cause of many pathologies in humans including, atrophic gastritis, gastric and duodenal ulcers, gastric mucosa-associated lymphoma and gastric cancer. Previous studies demonstrated that it is MUC1 on haematopoietic cells that plays a critical protective role during H. pylori-induced gastritis. MUC1 dampened the production of the pro-inflammatory cytokine IL-1β by suppressing activation of the NLRP3 inflammasome in immune cells, thereby protecting mice from severe H. pylori-associated disease. The current thesis was aimed at extending these findings by identifying the immune cell subset(s) in which MUC1 modulates the activation of the NLRP3 inflammasome in mice to protect against H. pylori pathogenesis and to evaluate the importance of this finding in a pulmonary bacterial infection model and in the function of human immune cells. Using an in vivo mice model of H. pylori infection, it was shown that MUC1 on monocytes and macrophages of the gastric mucosa negatively modulates NLRP3 inflammasome activation induced by H. pylori infection in mice. During investigations of the role of MUC1 during infection with the NLRP3-activating respiratory bacterial pathogen Streptococcus pneumoniae, a completely novel function of MUC1 on macrophages was discovered. Specifically, MUC1 was found to facilitate pneumococcal phagocytosis by murine macrophages, assisting in protection against pneumococcal pneumonia and bacteraemia. Thus, using two different pathogens at two different site, the studies presented in this thesis have identified that MUC1 has at least two quite distinct functions on macrophages which contributes to host defence against important mucosal bacterial pathogens. Another salient finding of this thesis is that MUC1 length, and not just the cytoplasmic domain, can affect the production of IL-1β in response to NLRP3 inflammasome activation. The length of MUC1 was not previously considered to have any direct effect on cytoplasmic immune signalling; this thesis now provides evidence to suggest the opposite, opening up a new area of future research. An interesting discovery made by studies in this thesis is the apparent function of MUC1 on eosinophils. Eosinophils are present in the immune cell infiltrate in the gastric mucosa of humans and mice, however their functional significance in H. pylori-associated disease is unknown. In the current thesis, H. pylori infection was found to induce caspase-1 activation in eosinophils, suggesting that these cells may be the source of IL-1β during H. pylori infection. MUC1 on these cells was found to function as a suppressor of caspase-1 activation, demonstrating a novel function of this molecule in eosinophils. In conclusion, studies presented in this thesis have clearly demonstrated that MUC1 specifically on macrophages and eosinophils plays a protective role during innate defences against bacterial pathogens. Thus, this study has added to the previously known functions of MUC1 and laid foundation for future studies to investigate the impact of MUC1 regulation of the aforementioned macrophage functions on infectious and non-infectious inflammatory diseases. Additionally, the possibility of an immunomodulatory role of MUC1 on eosinophils has opened up a new exciting area of research.
Subject mucin1, helicobacter, streptococcus, NLRP3 inflammasome, VNTR polymorphisms, macrophages