The Mucin Muc1 Suppresses Helicobacter pylori-induced Gastritis by Regulating the NLRP3 Inflammasome

BACKGROUND: Expression of the mucin MUC1 by epithelial cells is a critical component of the barrier lining the mucosal surface of the gastrointestinal tract. Polymorphisms in MUC1 are linked to increased susceptibility to gastric cancer caused by infection with the mucosal pathogen, Helicobacter pylori. Previously, we have shown, using MUC1 (Muc1^-/-) deficient mice, that this mucin plays an important role in suppressing H. pylori-induced gastritis, though the mechanism by which this occurs was unknown. 

RESULTS: Using bone marrow chimeras, we surprisingly found regulation of H. pylori-induced gastritis is not mediated by MUC1-expressing epithelial cells, but rather depends on mucin expression by immune cells. Severe gastritis in Muc1^-/- mice was associated with significant mucosal IL-1ß, and bacteria-stimulated Muc1^-/- cells secreted increased IL-1ß and IL-18. Hypothesising that MUC1 regulates an inflammasome, we used specific ligands to demonstrate that MUC1 specifically suppresses activation of the NLRP3 inflammasome, but not other complexes. Further analyses revealed MUC1 controls the expression of NLRP3 itself, via an interaction with the NF-kB pathway at the level of IRAK4 or above. Infection of Muc1^-/-xCaspase-1^-/- and Muc1^-/-xNlrp3^-/- double knock-out mice showed that the severe H. pylori-induced gastritis observed in Muc1^-/- mice was both caspase-1 and NLRP3 dependent. Flow cytometric analysis revealed neutrophils and dendritic cells as 1) the main cell-types infiltrating the infected Muc1^-/- gastric mucosa, 2) the predominant cells expressing active caspase-1.

CONCLUSION: This study demonstrates the important and previously unrecognised role that MUC1-expression by mucosal immune cells has in regulating bacterial-driven inflammation, via regulation of the NLRP3 inflammasome.