中性粒细胞胞外陷阱
先天性中性粒细胞减少
中性粒细胞弹性蛋白酶
髓过氧化物酶
生物
细胞外
中性粒细胞减少症
白色念珠菌
免疫学
转染
弹性蛋白酶
粒细胞
微生物学
佛波
分子生物学
基因
细胞生物学
炎症
酶
生物化学
遗传学
激酶
蛋白激酶C
化疗
作者
Avinash Khandagale,Beatrice Lazzaretto,Göran Carlsson,Mikael Sundin,Sulman Shafeeq,Ute Römling,Bengt Fadeel
标识
DOI:10.1002/jlb.4a0118-030rr
摘要
Abstract 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.
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