The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome

Ng, Garrett Z., Menheniott, Trevelyan R., Every, Alison L., Stent, Andrew, Judd, Louise M., Chionh, Yok Teng, Dhar, Poshmaal, Komen, Jasper C., Giraud, Andrew S., Wang, Timothy C., McGuckin, Michael A. and Sutton, Philip (2015) The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome. Gut, 1-13. doi:10.1136/gutjnl-2014-307175


Author Ng, Garrett Z.
Menheniott, Trevelyan R.
Every, Alison L.
Stent, Andrew
Judd, Louise M.
Chionh, Yok Teng
Dhar, Poshmaal
Komen, Jasper C.
Giraud, Andrew S.
Wang, Timothy C.
McGuckin, Michael A.
Sutton, Philip
Title The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome
Formatted title
The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome
Journal name Gut   Check publisher's open access policy
ISSN 1468-3288
0017-5749
Publication date 2015-04-08
Sub-type Article (original research)
DOI 10.1136/gutjnl-2014-307175
Start page 1
End page 13
Total pages 13
Place of publication London, United Kingdom
Publisher B M J Group
Collection year 2016
Language eng
Formatted abstract
Objectives: The mucin MUC1, best known for providing an epithelial barrier, is an important protective host factor in both humans and mice during Helicobacter pylori pathogenesis. This study aimed to identify the long-term consequences of MUC1 deficiency on H. pylori pathogenesis and the mechanism by which MUC1 protects against H. pylori gastritis.

Design: Wildtype and Muc1−/− mice were infected for up to 9 months, and the gastric pathology, immunological response and epigenetic changes assessed. The effects of MUC1 on the inflammasome, a potent inflammatory pathway, were examined in macrophages and H. pylori-infected mice deficient in both MUC1 and inflammasome components.

Results: Muc1−/− mice began to die 6 months after challenge, indicating Muc1 deficiency made H. pylori a lethal infection. Surprisingly, chimaeric mouse infections revealed MUC1 expression by haematopoietic-derived immune cells limits H. pylori-induced gastritis. Gastritis in infected Muc1−/− mice was associated with elevated interleukin (IL)-1β and epigenetic changes in their gastric mucosa similar to those in transgenic mice overexpressing gastric IL-1β, implicating MUC1 regulation of an inflammasome. In support of this, infected Muc1−/−Casp1−/− mice did not develop severe gastritis. Further, MUC1 regulated Nlrp3 expression via an nuclear factor (NF)-κB-dependent pathway and reduced NF-κB pathway activation via inhibition of IRAK4 phosphorylation. The importance of this regulation was proven using Muc1−/−Nlrp3−/− mice, which did not develop severe gastritis.

Conclusions: MUC1 is an important, previously unidentified negative regulator of the NLRP3 inflammasome. H. pylori activation of the NLRP3 inflammasome is normally tightly regulated by MUC1, and loss of this critical regulation results in the development of severe pathology.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Official 2016 Collection
UQ Diamantina Institute Publications
 
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