Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation

Jennifer L. Johnson, Elsa Meneses-Salas, Mahalakshmi Ramadass, Jlenia Monfregola, Farhana Rahman, Raquel Carvalho Gontijo, William B. Kiosses, Kersi Pestonjamasp, Dale Allen, Jinzhong Zhang, Douglas G. Osborne, Yanfang Peipei Zhu, Nathan Wineinger, Kasra Askari, Danni Chen, Juan Yu, Scott C. Henderson, Catherine C. Hedrick, Matilde Valeria Ursini, Sergio Grinstein, Daniel D. Billadeau and Sergio D. Catz ()
Additional contact information
Jennifer L. Johnson: The Scripps Research Institute
Elsa Meneses-Salas: The Scripps Research Institute
Mahalakshmi Ramadass: The Scripps Research Institute
Jlenia Monfregola: The Scripps Research Institute
Farhana Rahman: The Scripps Research Institute
Raquel Carvalho Gontijo: The Scripps Research Institute
William B. Kiosses: La Jolla Institute for Immunology
Kersi Pestonjamasp: The Scripps Research Institute
Dale Allen: The Scripps Research Institute
Jinzhong Zhang: The Scripps Research Institute
Douglas G. Osborne: Schulze Center for Novel Therapeutics, Mayo Clinic
Yanfang Peipei Zhu: La Jolla Institute for Immunology
Nathan Wineinger: The Scripps Research Institute
Kasra Askari: The Scripps Research Institute
Danni Chen: The Scripps Research Institute
Juan Yu: The Scripps Research Institute
Scott C. Henderson: The Scripps Research Institute
Catherine C. Hedrick: La Jolla Institute for Immunology
Matilde Valeria Ursini: Institute of Genetics and Biophysics A. Buzzati Traverso CNR
Sergio Grinstein: University of Toronto
Daniel D. Billadeau: Schulze Center for Novel Therapeutics, Mayo Clinic
Sergio D. Catz: The Scripps Research Institute

Nature Communications, 2022, vol. 13, issue 1, 1-24

Abstract: Abstract 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 impaired exocytosis. Rac1 activation restores exocytosis of these granules. In vivo, WASH deficiency induces exacerbated azurophilic granule exocytosis, inflammation, and decreased survival. WASH deficiency thus differentially impacts neutrophil granule subtypes, impairing exocytosis of granules that mediate the initiation of the neutrophil innate response while exacerbating pro-inflammatory granule secretion.

Date: 2022
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DOI: 10.1038/s41467-022-33230-y

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