JAGN1 is required for fungal killing in neutrophil extracellular traps: Implications for severe congenital neutropenia
| Autor: | Göran Carlsson, Beatrice Lazzaretto, Mikael Sundin, Ute Römling, Avinash Khandagale, Bengt Fadeel, Sulman Shafeeq |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Neutropenia Filgrastim Neutrophils Immunology HL-60 Cells Transfection Extracellular Traps Microbiology 03 medical and health sciences Candida albicans Immunology and Allergy Congenital Bone Marrow Failure Syndromes Humans RNA Messenger RNA Small Interfering Congenital Neutropenia Peroxidase biology Granulocyte-Macrophage Colony-Stimulating Factor Membrane Proteins Cell Biology Neutrophil extracellular traps biology.organism_classification 3. Good health Chromatin 030104 developmental biology Myeloperoxidase Neutrophil elastase Child Preschool biology.protein Tetradecanoylphorbol Acetate RNA Interference Calprotectin |
| Zdroj: | Journal of Leukocyte Biology |
| ISSN: | 0741-5400 |
| DOI: | 10.1002/jlb.4a0118-030rr |
| Popis: | 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. The present study explores the role of JAGN1 for the candidacidal function of neutrophil extracellular traps, with implications for severe congenital neutropenia. |
| Databáze: | OpenAIRE |
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