title: Granzyme M has a critical role in providing innate immune protection in ulcerative colitis.
abstract: Inflammatory bowel disease (IBD) is an immunoregulatory disorder, associated with a chronic and inappropriate mucosal immune response to commensal bacteria, underlying disease states such as ulcerative colitis (UC) and Crohn's disease (CD) in humans. Granzyme M (GrzM) is a serine protease expressed by cytotoxic lymphocytes, in particular natural killer (NK) cells. Granzymes are thought to be involved in triggering cell death in eukaryotic target cells; however, some evidence supports their role in inflammation. The role of GrzM in the innate immune response to mucosal inflammation has never been examined. Here, we discover that patients with UC, unlike patients with CD, display high levels of GrzM mRNA expression in the inflamed colon. By taking advantage of well-established models of experimental UC, we revealed that GrzM-deficient mice have greater levels of inflammatory indicators during dextran sulfate sodium (DSS)-induced IBD, including increased weight loss, greater colon length reduction and more severe intestinal histopathology. The absence of GrzM expression also had effects on gut permeability, tissue cytokine/chemokine dynamics, and neutrophil infiltration during disease. These findings demonstrate, for the first time, that GrzM has a critical role during early stages of inflammation in UC, and that in its absence colonic inflammation is enhanced.
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.|Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria 3010, Australia.|Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Souza-Fonseca-Guimaraes
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.|School of Medicine, University of Queensland, St Lucia, Queensland 4006, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Krasnova
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Putoczki
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Miles
authors.affiliation: Antigen Presentation and Immunoregulation Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: K P
authors.initials: KP
authors.lastname: MacDonald
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Town
authors.affiliation: Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.affiliation: Centre for Kidney Disease Research, School of Medicine, University of Queensland at Translational Research Institute, St Lucia, Queensland 4006, Australia.
authors.forename: G C
authors.initials: GC
authors.lastname: Gobe
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.
authors.forename: L
authors.initials: L
authors.lastname: McDade
authors.affiliation: Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: Mielke
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Tye
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: G T
authors.initials: GT
authors.lastname: Belz
authors.affiliation: Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: N D
authors.initials: ND
authors.lastname: Huntington
authors.affiliation: Inflammatory Bowel Disease Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.|Department of Gastroenterology, Royal Brisbane and Women's Hospital, Herston, Queensland 4006, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Radford-Smith
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.|School of Medicine, University of Queensland, St Lucia, Queensland 4006, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D015870:Gene Expression; D053804:Granzymes / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D010539:Permeability; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology
chemical_list: D012333:RNA, Messenger; D016264:Dextran Sulfate; C509218:GZMM protein, human; D053804:Granzymes; C509219:Gzmm protein, mouse