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GSDMD drives canonical inflammasome-induced neutrophil pyroptosis and is dispensable for NETosis


ABSTRACT: Neutrophils are the most prevalent immune cells in circulation, but the repertoire of canonical inflammasomes in neutrophils and their respective involvement in neutrophil IL-1β secretion and neutrophil cell death remains unclear. Here, we show that neutrophil-targeted expression of the disease-associated gain-of-function Nlrp3 A350V mutant suffices for systemic autoinflammatory disease and tissue pathology in vivo. We confirm activity of the canonical NLRP3 and NLRC4 inflammasomes, and further show that the NLRP1b, Pyrin and AIM2 inflammasomes in neutrophils also promote maturation and secretion of interleukin (IL)-1β in cultured bone marrow neutrophils. Notably, all tested canonical inflammasomes promote GSDMD cleavage. Furthermore,canonical inflammasome-induced pyroptosis and secretion of mature IL-1β are blunted in GSDMD knockout neutrophils. In contrast, GSDMD is dispensable for PMA-induced NETosis. We also show that Salmonella Typhimurium-induced pyroptosis is markedly increased in Nox2/Gp91Phox-deficient neutrophils that lack NADPH oxidase activity and are defective in PMA-induced NETosis. In conclusion, we establish the canonical inflammasome repertoire in neutrophils, and identify differential roles for GSDMD and the NADPH complex in canonical inflammasome-induced neutrophil pyroptosis and mitogen-induced NETosis, respectively.

SUBMITTER: Dr. Dhruv Chauhan 

PROVIDER: S-SCDT-EMBOR-2021-54277V1 | biostudies-other |

REPOSITORIES: biostudies-other

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