Caspase-1-driven neutrophil pyroptosis promotes an incomplete NETosis upon Pseudomonas aeruginosa infection
| Autor: | Serge Mazères, Stephen Adonai Leon-Icaza, Mohamed Lamkanfi, Karin Santoni, Christine T.N. Pham, Jean-Philippe Girard, Etienne Meunier, Emilie Doz-Deblauwe, Audrey Hessel, Odile Burlet-Schiltz, Christophe Paget, David Péricat, Aylward F, Yoann Rombouts, Anne Gonzalez-de-Peredo, Salimata Bagayoko, Nathalie Winter, Renaud Poincloux, Pierre-Jean Bordignon, Céline Cougoule, Rémi Planès, Emma Lefrançais, Elisabeth Bellard, Miriam Pinilla, Abdderrahim R |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
biology Chemistry medicine.medical_treatment Pyroptosis Caspase 1 Inflammasome Inflammation Phospholipase 3. Good health Cell biology 03 medical and health sciences 0302 clinical medicine Histone Cytokine NLRC4 medicine biology.protein medicine.symptom 030217 neurology & neurosurgery 030304 developmental biology medicine.drug |
| Popis: | Multiple neutrophil death programs contribute to host defense against infections. Although expressing all necessary components, neutrophils specifically fail to undergo pyroptosis, a lytic form of cell death triggered by the activation of the pro-inflammatory complex inflammasome. In the light of the arm race, we hypothesized that intrinsic neutrophil pyroptosis resistance might be bypassed in response to specific microbial species. We show that Pseudomonas aeruginosa (P. aeruginosa) stimulates Caspase-1-dependent pyroptosis in human and murine neutrophils. Mechanistically, activated NLRC4 inflammasome supports Caspase-1-driven Gasdermin-D (GSDMD) activation, IL-1β cytokine release and neutrophil pyroptosis. Furthermore, GSDMD activates Peptidyl Arginine Deaminase-4 which drives an “incomplete NETosis” where neutrophil DNA fills the cell cytosol but fails crossing plasma membrane. Finally, we show that neutrophil Caspase-1 account for IL-1β production and contributes to various P. aeruginosa strains spread in mice. Overall, we demonstrate that neutrophils are fully competent for Caspase-1-dependent pyroptosis, which drives an unsuspected “incomplete NETosis”.SummaryNeutrophils play an essential roles against infections. Although multiple neutrophil death programs contribute to host defense against infections, they fail to undergo pyroptosis, a pro-inflammatory form of cell death. Upon Infections, pyroptosis can be induced in macrophages or epithelial cells upon activation of pro-inflammatory complexes, inflammasomes that trigger Caspase-1-driven Gasdermin dependent plasma membrane lysis. In the light of host-microbe interactions, we hypothesized that yet to find microbial species might hold the capacity to overcome neutrophil resistance to inflammasome-driven pyroptosis. Among several bacterial species, we describe that the bacterium Pseudomonas aeruginosa specifically engages the NLRC4 inflammasome, which promotes Caspase-1-dependent Gasdermin-D activation and subsequent neutrophil pyroptosis. Furthermore, inflammasome-driven pyroptosis leads to DNA decondensation and expansion into the host cell cytosol but not to the so called Neutrophil Extracellular Trap (NET) release as DNA fails breaching the plasma membrane. Finally, in vivo P. aeruginosa infections highlight that Caspase-1-driven neutrophil pyroptosis is functional and is detrimental upon P. aeruginosa infection. Altogether, our results unexpectedly underline neutrophil competence for Caspase-1-dependent pyroptosis, a process that contributes to host susceptibility to P. aeruginosa infection. |
| Databáze: | OpenAIRE |
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