title: Protease-activated receptor 1 suppresses Helicobacter pylori gastritis via the inhibition of macrophage cytokine secretion and interferon regulatory factor 5.
abstract: Chronic gastritis from Helicobacter pylori infection is a major factor in the development of gastric adenocarcinoma. Factors that regulate gastritis severity are important in determining which individuals are susceptible to H. pylori-associated disease. Although protease-activated receptor 1 (PAR1) has been identified as one such host factor, its mechanism of action is unknown. Using chimeric mice, we demonstrated that PAR1-mediated protection against H. pylori gastritis requires bone marrow-derived cells. Analyses of the gastric mucosa revealed that PAR1 suppresses cellular infiltration and both T helper type 1 (Th1) and T helper type 17 (Th17) responses to infection. Moreover, PAR1 expression was associated with reduced vaccine-mediated protection against H. pylori. Analyses of H. pylori-stimulated macrophages revealed that PAR1 activation suppressed secretion of interleukin (IL)-12 and IL-23, key drivers of Th1 and Th17 immunity, respectively. Furthermore, PAR1 suppressed interferon regulatory factor 5 (IRF5), an important transcription factor for IL-12 and IL-23, both in the infected mucosa and following bacterial stimulation. PAR1 suppression of IRF5 and IL-12/23 secretion by macrophages provides a novel mechanism by which the host suppresses the mucosal Th1 and Th17 response to H. pylori infection. Dysregulation of this process is likely an important factor in the susceptibility of some individuals to H. pylori-associated disease.
authors.affiliation: 1] Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Melbourne, Victoria, Australia [2] Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Chionh
authors.affiliation: 1] Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Melbourne, Victoria, Australia [2] Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: G Z
authors.initials: GZ
authors.lastname: Ng
authors.affiliation: Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Ong
authors.affiliation: Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Arulmuruganar
authors.affiliation: Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Stent
authors.affiliation: 1] Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Melbourne, Victoria, Australia [2] Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Saeed
authors.affiliation: Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: J Lk
authors.initials: JL
authors.lastname: Wee
authors.affiliation: 1] Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Melbourne, Victoria, Australia [2] Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Sutton
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D002678:Chimera; D002908:Chronic Disease; D005756:Gastritis / Q000235:genetics* / Q000382:microbiology*; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D050835:Interferon Regulatory Factors; D053759:Interleukin-23; C498178:Irf5 protein, mouse; D044463:Receptor, PAR-1; D018664:Interleukin-12