BACKGROUND: Muc1 is a cell surface mucin expressed by epithelial cells lining the gastrointestinal tract, which is best known for its role in the mucosal barrier. We have previously demonstrated Muc1 to be a key regulator of gastritis induced by the mucosal pathogen Helicobacter pylori, the main cause of gastric cancer.
RESULTS: During long-term experiments, H.pylori infected Muc1-/- mice had a survival rate of <50% 6 months post infection, while wildtype mice remain asymptomatic. Bone marrow chimaera studies revealed that Muc1 regulation of H. pylori-induced gastritis is mediated by haematopoietic and not epithelial cells, indicating a critical role for immune cell expression of Muc1. The gastric mucosa of H. pylori infected Muc1-/- mice contains significantly elevated levels of IL-1ß and in vitro studies showed Muc1-/- macrophages produce elevated IL-1ß levels upon stimulation, compared to wildtype cells. This association with IL-1ß implied a link between Muc1 and the inflammasome. By the use of specific inflammasome activators, we identified that Muc1 selectively regulates activation of the NLRP3 inflammasome. The role of Muc1 in regulating the NLRP3 inflammasome was confirmed by infection experiments involving Muc1-/- caspase1-/- and Muc1-/- Nlrp3-/- double knock-out mice.
CONCLUSION: We conclude that Muc1 presence on immune cells suppresses IL-1β secretion via negative regulation of the Nlrp3 inflammasome, thus affecting H.pylori-induced pathologies.