title: The MUC1 mucin protects against Helicobacter pylori pathogenesis in mice by regulation of the NLRP3 inflammasome.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Garrett Z
authors.initials: GZ
authors.lastname: Ng
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Trevelyan R
authors.initials: TR
authors.lastname: Menheniott
authors.affiliation: Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Every
authors.affiliation: Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stent
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Judd
authors.affiliation: Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Yok Teng
authors.initials: YT
authors.lastname: Chionh
authors.affiliation: Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Poshmaal
authors.initials: P
authors.lastname: Dhar
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Jasper C
authors.initials: JC
authors.lastname: Komen
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Giraud
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Mucosal Diseases Program, Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.affiliation: Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Sutton
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism; D005756:Gastritis / Q000382:microbiology* / Q000473:pathology; D015870:Gene Expression; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D058847:Inflammasomes / Q000378:metabolism*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D000071164:Trefoil Factor-2 / Q000235:genetics
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D018396:Mucin-1; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C000604007:TFF2 protein, human; D000071164:Trefoil Factor-2; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse; D020170:Caspase 1
keywords: GASTRIC CANCER; HELICOBACTER PYLORI - GASTRITIS; INFLAMMATORY MECHANISMS; MUCINS