Garrett Z Ng1, Trevelyan R Menheniott2, Alison L Every3, Andrew Stent3, Louise M Judd2, Yok Teng Chionh3, Poshmaal Dhar1, Jasper C Komen2, Andrew S Giraud2, Timothy C Wang4, Michael A McGuckin5, Philip Sutton1. 1. 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. 2. Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia. 3. Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia. 4. Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, USA. 5. Mucosal Diseases Program, Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVES: The mucinMUC1, 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. pylorigastritis. 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 infectedMuc1(-/-) 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Kosuke Kato; Alec D Hanss; Marina A Zemskova; Nicole E Morgan; Marianne Kim; Kenneth S Knox; Yong Lin; Erik P Lillehoj; Kwang Chul Kim Journal: Biochem Biophys Res Commun Date: 2017-08-16 Impact factor: 3.575
Authors: Trevelyan R Menheniott; Louise O'Connor; Yok Teng Chionh; Jan Däbritz; Michelle Scurr; Benjamin N Rollo; Garrett Z Ng; Shelley Jacobs; Angelique Catubig; Bayzar Kurklu; Stephen Mercer; Toshinari Minamoto; David E Ong; Richard L Ferrero; James G Fox; Timothy C Wang; Philip Sutton; Louise M Judd; Andrew S Giraud Journal: J Clin Invest Date: 2016-03-14 Impact factor: 14.808