Science Bite - 3 min Oral Presentation (Students and ECRs only) Lorne Infection and Immunity 2020

Disparate functions of mucin 1 (MUC1) during bacterial infections and inflammation.   (#59)

Poshmaal Dr Dhar 1 , Garrett Dr Ng 2 , Eileen Dr Dunne 3 , Phil Professor Sutton 3
  1. Deakin University, Waurn Ponds, VIC, Australia
  2. Department of Biochemistry and Molecular Biology , The University of Melbourne, MELBOURNE, VICTORIA, Australia
  3. Murdoch Children's Research Institute, MELBOURNE, VICTORIA, Australia

Mucin 1 (MUC1) is a cell membrane-associated glycoprotein, expressed on epithelial cells and immune cells. MUC1 on epithelial surfaces can protect against pathogens by two mechanisms: 1) MUC1 limits the access of pathogens to the epithelium, and; 2) MUC1 down-regulates Toll-like receptor signalling, suppressing the production of pro-inflammatory cytokines, thereby reducing inflammation and resultant pathology. We have previously shown that MUC1 on hematopoietic cells protects against the gastric pathogen, Helicobacter pylori by dampening IL-1β production via repression of the NLRP3 inflammasome1. The current study was undertaken to unravel the identity and function of MUC1 on these immune cells.

Wildtype (WT) and Muc1-knockout (Muc1-/-) mice were infected with H. pylori for two months. Multicolour flow cytometry was used to phenotype the immune cell infiltrate in the stomachs of infected mice. NLRP3 inflammasome activation was measured by quantifying caspase-1. While H. pylori infection induced caspase-1 activation in gastric neutrophil and dendritic cells of both WT and Muc1-/- mice, monocyte/macrophage subsets from Muc1-/- mice displayed increased caspase-1 activation compared to control mice. Further investigations on this immune-modulatory role of MUC1 on macrophages during infection by another NLRP3-activating pathogen, S. pneumoniae, revealed a completely novel function of MUC1 on macrophages. Using in vitro phagocytosis assays, MUC1 was found to facilitate pneumococcal phagocytosis by macrophages, assisting in protection against pneumococcal pneumonia and bacteraemia in mice2. The clinical implications of these findings were investigated in vitro using human PBMCs, providing the first evidence of an immune-modulatory role of MUC1 polymorphisms in human macrophages3.

  

1. Ng, G. Z. et al. The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome. Gut 65, 1087, doi:10.1136/gutjnl-2014-307175 (2016).

2. Dhar, P., Ng, G. Z., Dunne, E. M. & Sutton, P. Mucin 1 protects against severe Streptococcus pneumoniae infection. Virulence 8, 1631-1642, doi:10.1080/21505594.2017.1341021 (2017).

3. Dhar, P. et al. Effect of MUC1 length polymorphisms on the NLRP3 inflammasome response of human macrophages. Human Immunology, doi:https://doi.org/10.1016/j.humimm.2019.06.001 (2019).