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JAGN1 is required for fungal killing in neutrophil extracellular traps: Implications for severe congenital neutropenia
Author(s) -
Khandagale Avinash,
Lazzaretto Beatrice,
Carlsson Göran,
Sundin Mikael,
Shafeeq Sulman,
Römling Ute,
Fadeel Bengt
Publication year - 2018
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.4a0118-030rr
Subject(s) - neutrophil extracellular traps , congenital neutropenia , neutrophil elastase , myeloperoxidase , biology , extracellular , neutropenia , candida albicans , immunology , transfection , elastase , granulocyte , microbiology and biotechnology , phorbol , gene , inflammation , enzyme , biochemistry , genetics , kinase , protein kinase c , chemotherapy
Mutations in the gene JAGN1 were recently discovered in patients with severe congenital neutropenia (SCN). Neutrophils release neutrophil extracellular traps (NETs) consisting of decondensed chromatin decorated with various granular proteins such as neutrophil elastase and myeloperoxidase (MPO) to combat microbial infections. However, whether JAGN1 is required for the formation or function of NETs is not known. Here, we analyzed primary neutrophils from a patient with homozygous JAGN1 mutations with respect to phorbol myristate acetate (PMA)‐induced NET formation. NET release was observed, but there appeared to be a reduced level of expression of MPO in the NETs. To study this further, we differentiated HL‐60 cells into neutrophil‐like cells and silenced JAGN1 expression by transfection with siRNA. These cells remained capable of producing NETs, but MPO expression was severely affected, and NETs released by JAGN1 ‐silenced cells were ineffective in killing Candida albicans . The candidacidal function was restored upon treatment with GM‐CSF or addition of MPO. GM‐CSF also up‐regulated the expression of calprotectin in NETs. Notably, JAGN1 did not impact on N‐glycosylation of MPO in neutrophil‐like HL‐60 cells. These studies shed light on the susceptibility of SCN patients to fungal infections and the role of JAGN1 for the antimicrobial function of neutrophils exerted by NETs.