Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins

Sylwia D. Tyrkalska, Sergio Candel, Diego Angosto, Victoria Gómez-Abellán, Fátima Martín-Sánchez, Diana García-Moreno, Rubén Zapata-Pérez, Álvaro Sánchez-Ferrer, María P. Sepulcre, Pablo Pelegrín and Victoriano Mulero ()
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Sylwia D. Tyrkalska: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca
Sergio Candel: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca
Diego Angosto: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca
Victoria Gómez-Abellán: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca
Fátima Martín-Sánchez: Unidad de inflamación y Cirugía Experimental, CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca
Diana García-Moreno: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca
Rubén Zapata-Pérez: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca
Álvaro Sánchez-Ferrer: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca
María P. Sepulcre: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca
Pablo Pelegrín: Unidad de inflamación y Cirugía Experimental, CIBERehd, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB-Arrixaca
Victoriano Mulero: Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca

Nature Communications, 2016, vol. 7, issue 1, 1-17

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12077

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