Caspase-1-driven neutrophil pyroptosis and its role in host susceptibility to Pseudomonas aeruginosa

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Santoni, Karin | Pericat, David | Gorse, Leana | Buyck, Julien | Pinilla, Miriam | Prouvensier, Laure | Bagayoko, Salimata | Hessel, Audrey | Leon-Icaza, Stephen Adonai | Bellard, Elisabeth | Mazères, Serge | Doz-Deblauwe, Emilie | Winter, Nathalie | Paget, Christophe | Girard, Jean-Philippe | Pham, Christine T.N. | Cougoule, Céline | Poincloux, Renaud | Lamkanfi, Mohamed | Lefrancais, Emma | Meunier, Etienne | Planès, Rémi

Edité par CCSD ; Public Library of Science -

International audience. Multiple regulated neutrophil cell death programs contribute to host defense against infections. However, despite expressing all necessary inflammasome components, neutrophils are thought to be generally defective in Caspase-1-dependent pyroptosis. By screening different bacterial species, we found that several Pseudomonas aeruginosa ( P . aeruginosa ) strains trigger Caspase-1-dependent pyroptosis in human and murine neutrophils. Notably, deletion of Exotoxins U or S in P . aeruginosa enhanced neutrophil death to Caspase-1-dependent pyroptosis, suggesting that these exotoxins interfere with this pathway. Mechanistically, P . aeruginosa Flagellin activates the NLRC4 inflammasome, which supports Caspase-1-driven interleukin (IL)-1β secretion and Gasdermin D (GSDMD)-dependent neutrophil pyroptosis. Furthermore, P . aeruginosa -induced GSDMD activation triggers Calcium-dependent and Peptidyl Arginine Deaminase-4-driven histone citrullination and translocation of neutrophil DNA into the cell cytosol without inducing extracellular Neutrophil Extracellular Traps. Finally, we show that neutrophil Caspase-1 contributes to IL-1β production and susceptibility to pyroptosis-inducing P . aeruginosa strains in vivo . Overall, we demonstrate that neutrophils are not universally resistant for Caspase-1-dependent pyroptosis.

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