biostudies-literatureJohnson JLNIDDK NIH HHSCystinosis Research FoundationNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin DiseasesU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstituteNIAMS NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases5529https://www.ebi.ac.uk/biostudies/studies/S-EPMC9492659biostudies-literatureUnknown13(1)Dysregulated secretion in neutrophil leukocytes associates with human inflammatory disease. The exocytosis response to triggering stimuli is sequential; gelatinase granules modulate the initiation of the innate immune response, followed by the release of pro-inflammatory azurophilic granules, requiring stronger stimulation. Exocytosis requires actin depolymerization which is actively counteracted under non-stimulatory conditions. Here we show that the actin nucleator, WASH, is necessary to maintain azurophilic granules in their refractory state by granule actin entrapment and interference with the Rab27a-JFC1 exocytic machinery. On the contrary, gelatinase granules of WASH-deficient neutrophil leukocytes are characterized by decreased Rac1, shortened granule-associated actin comets and impNature communicationsDifferential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation.PMC9492659R01AR070837R01 AR070837P01HL152958CRFS2020-001P01 HL152958R01DK110162R01 HL088256R01HL088256R01 DK110162Wineinger NJohnson JLRahman FZhang JCarvalho Gontijo RKiosses WBBilladeau DDMeneses-Salas EMonfregola JYu JUrsini MVHedrick CCRamadass MAllen DChen DCatz SDAskari KZhu YPOsborne DGGrinstein SHenderson SCPestonjamasp KfalseDifferential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation.Dysregulated secretion in neutrophil leukocytes associates with human inflammatory disease. The exocytosis response to triggering stimuli is sequential; gelatinase granules modulate the initiation of the innate immune response, followed by the release of pro-inflammatory azurophilic granules, requiring stronger stimulation. Exocytosis requires actin depolymerization which is actively counteracted under non-stimulatory conditions. Here we show that the actin nucleator, WASH, is necessary to maintain azurophilic granules in their refractory state by granule actin entrapment and interference with the Rab27a-JFC1 exocytic machinery. On the contrary, gelatinase granules of WASH-deficient neutrophil leukocytes are characterized by decreased Rac1, shortened granule-associated actin comets and imp2022-01-01T00:00:00Z2022 Sep2026-07-14T15:49:28.363Z2025-04-04T09:30:02.244ZS-EPMC94926593613097110.1038/s41467-022-33230-y