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

• Published in: Nature communications Vol. 7; no. 1; p. 12077
• Main Authors: Tyrkalska, Sylwia D., Candel, Sergio, Angosto, Diego, Gómez-Abellán, Victoria, Martín-Sánchez, Fátima, García-Moreno, Diana, Zapata-Pérez, Rubén, Sánchez-Ferrer, Álvaro, Sepulcre, María P., Pelegrín, Pablo, Mulero, Victoriano
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 14/34; 38/77; 42; 42/109; 59; 631/250/2504/223/1699; 631/250/255/1318; 631/250/256/2177; 64/116; 692/308; 82/29; 82/80; Adapters; Animals; Bacteria; Bacterial infections; Biosynthesis; Caspase Activation and Recruitment Domain; Cell activation; GTP-Binding Proteins - immunology; Guanosine triphosphatases; Guanylate-binding protein; Humanities and Social Sciences; Immune clearance; Immune system; Infections; Inflammasomes; Inflammasomes - immunology; Interleukin-8 - immunology; Leukocytes (neutrophilic); Leukotriene B4; Leukotriene B4 - immunology; Morpholinos; multidisciplinary; Neutrophils; Neutrophils - immunology; Organisms, Genetically Modified; Prostaglandin D2; Prostaglandin D2 - biosynthesis; Prostaglandins; Prostaglandins - immunology; Proteins; Salmonella; Salmonella typhimurium; Science; Science (multidisciplinary); Zebrafish; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12077

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.
The role of guanylate-binding proteins (GBPs) in innate immunity is increasingly recognized. Here the authors show that GBP4 activates inflammasome in zebrafish neutrophils, and that this process is critical for the clearance of
Salmonella
infection via prostaglandin D2.