TY - JOUR
T1 - Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation
AU - Johnson, Jennifer L.
AU - Meneses-Salas, Elsa
AU - Ramadass, Mahalakshmi
AU - Monfregola, Jlenia
AU - Rahman, Farhana
AU - Carvalho Gontijo, Raquel
AU - Kiosses, William B.
AU - Pestonjamasp, Kersi
AU - Allen, Dale
AU - Zhang, Jinzhong
AU - Osborne, Douglas G.
AU - Zhu, Yanfang Peipei
AU - Wineinger, Nathan
AU - Askari, Kasra
AU - Chen, Danni
AU - Yu, Juan
AU - Henderson, Scott C.
AU - Hedrick, Catherine C.
AU - Ursini, Matilde Valeria
AU - Grinstein, Sergio
AU - Billadeau, Daniel D.
AU - Catz, Sergio D.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-022-33230-y
DO - 10.1038/s41467-022-33230-y
M3 - Article
C2 - 36130971
AN - SCOPUS:85138277393
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5529
ER -