title: Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins.
abstract: Inflammasomes are cytosolic molecular platforms that alert the immune system about the presence of infection. Here we report that zebrafish guanylate-binding protein 4 (Gbp4), an IFNγ-inducible GTPase protein harbouring a C-terminal CARD domain, is required for the inflammasome-dependent clearance of Salmonella Typhimurium (ST) by neutrophils in vivo. Despite the presence of the CARD domain, Gbp4 requires the universal inflammasome adaptor Asc for mediating its antibacterial function. In addition, the GTPase activity of Gbp4 is indispensable for inflammasome activation and ST clearance. Mechanistically, neutrophils are recruited to the infection site through the inflammasome-independent production of the chemokine (CXC motif) ligand 8 and leukotriene B4, and then mediate bacterial clearance through the Gbp4 inflammasome-dependent biosynthesis of prostaglandin D2. Our results point to GBPs as key inflammasome adaptors required for prostaglandin biosynthesis and bacterial clearance by neutrophils and suggest that transient activation of the inflammasome may be used to treat bacterial infections.
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.|Instituto de Investigaciones Marinas, CSIC, 36208 Vigo, Spain.
authors.forename: Sylwia D
authors.initials: SD
authors.lastname: Tyrkalska
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Candel
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Angosto
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gómez-Abellán
authors.affiliation: Unidad de inflamación y Cirugía Experimental, CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, 30120 Murcia, Spain.
authors.forename: Fátima
authors.initials: F
authors.lastname: Martín-Sánchez
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: García-Moreno
authors.affiliation: Facultad de Biología, Departamento de Bioquímica y Biología Molecular A, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Zapata-Pérez
authors.affiliation: Facultad de Biología, Departamento de Bioquímica y Biología Molecular A, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Sánchez-Ferrer
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
authors.forename: María P
authors.initials: MP
authors.lastname: Sepulcre
authors.affiliation: Unidad de inflamación y Cirugía Experimental, CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, 30120 Murcia, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Pelegrín
authors.affiliation: Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
authors.forename: Victoriano
authors.identifier: http://orcid.org/0000-0001-9527-0211
authors.initials: V
authors.lastname: Mulero
mesh_terms: D000818:Animals; D000071476:Caspase Activation and Recruitment Domain; D019204:GTP-Binding Proteins / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology*; D016209:Interleukin-8 / Q000276:immunology; D007975:Leukotriene B4 / Q000276:immunology; D060172:Morpholinos; D009504:Neutrophils / Q000276:immunology*; D030781:Organisms, Genetically Modified; D015230:Prostaglandin D2 / Q000096:biosynthesis*; D011453:Prostaglandins / Q000276:immunology; D012486:Salmonella typhimurium; D015027:Zebrafish
chemical_list: D058847:Inflammasomes; D016209:Interleukin-8; D060172:Morpholinos; D011453:Prostaglandins; D007975:Leukotriene B4; D019204:GTP-Binding Proteins; D015230:Prostaglandin D2