Molecular mechanisms of aberrant neutrophil differentiation in glycogen storage disease type Ib.

IF 1.2 3区社会学 Q3 SOCIOLOGY Berliner Journal Fur Soziologie Pub Date : 2022-04-18 DOI:10.1007/s00018-022-04267-5

Sang Wan Sim, Yuyeon Jang, Tae Sub Park, Byung-Chul Park, Young Mok Lee, Hyun Sik Jun

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Abstract

Glycogen storage disease type Ib (GSD-Ib), characterized by impaired glucose homeostasis, neutropenia, and neutrophil dysfunction, is caused by a deficiency in glucose-6-phosphate transporter (G6PT). Neutropenia in GSD-Ib has been known to result from enhanced apoptosis of neutrophils. However, it has also been raised that neutrophil maturation arrest in the bone marrow would contribute to neutropenia. We now show that G6pt^-/- mice exhibit severe neutropenia and impaired neutrophil differentiation in the bone marrow. To investigate the role of G6PT in myeloid progenitor cells, the G6PT gene was mutated using CRISPR/Cas9 system, and single cell-derived G6PT^-/- human promyelocyte HL-60 cell lines were established. The G6PT^-/- HL-60s exhibited impaired neutrophil differentiation, which is associated with two mechanisms: (i) abnormal lipid metabolism causing a delayed metabolic reprogramming and (ii) reduced nuclear transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ) in G6PT^-/- HL-60s. In this study, we demonstrated that G6PT is essential for neutrophil differentiation of myeloid progenitor cells and regulates PPARγ activity.

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糖原贮积病 Ib 型中性粒细胞异常分化的分子机制

糖原贮积病 Ib 型（GSD-Ib）以葡萄糖稳态受损、中性粒细胞减少和中性粒细胞功能障碍为特征，是由葡萄糖-6-磷酸转运体（G6PT）缺乏引起的。已知 GSD-Ib 中性粒细胞减少症是由于中性粒细胞凋亡增强所致。然而，也有人提出，中性粒细胞在骨髓中的成熟停滞也会导致中性粒细胞减少症。现在，我们发现 G6pt-/- 小鼠表现出严重的中性粒细胞减少症和骨髓中性粒细胞分化受损。为了研究 G6PT 在髓系祖细胞中的作用，我们使用 CRISPR/Cas9 系统突变了 G6PT 基因，并建立了单细胞衍生的 G6PT-/- 人原核细胞 HL-60 细胞系。G6PT-/- HL-60s表现出中性粒细胞分化障碍，这与两种机制有关：(i) 脂质代谢异常导致代谢重编程延迟；(ii) G6PT-/- HL-60s中过氧化物酶体增殖激活受体-γ（PPARγ）的核转录活性降低。在这项研究中，我们证明了 G6PT 对于髓系祖细胞的中性粒细胞分化至关重要，并能调节 PPARγ 的活性。

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来源期刊

Berliner Journal Fur Soziologie SOCIOLOGY-

CiteScore

1.80

自引率

27.30%

发文量

期刊介绍： Berliner Journal für Soziologie (“Berlin Journal of Sociology”), edited by the Institute of Sociology at the Friedrich Schiller University Jena and the Institute of Social Sciences at the Humboldt University Berlin, publishes double-blind peer-reviewed articles on classical and modern theoretical approaches, essays on current problem areas of sociological discourse, and research notes presenting new empirical findings. Focussed issues and review essays reflect innovative developments within the German and international social sciences and inform about the state of research in central areas of sociology. The journal was founded in 1991 on the initiative of the East German Society of Sociology. It views itself as a general sociological journal that publishes contributions from all research and subject areas of sociology. From the very beginning, the programmatic aim has been to provide a forum for the discussion and further development of sociological problems in the light of contemporary theoretical and social developments. Two major topics have been at the journal''s core and will continue to shape its contents in the future: Transformation and Culture. The journal deals with the socio-ecological upheaval that modern societies are undergoing. Globalisation, changes in working society and lifestyles, digitalisation, social conflicts up to new wars, new challenges for democracy, populism and nationalism as well as gender relations are important topics of a renewed Great Transformation. Cultural sociology and comparative cultural research deal with developments in these fields in a special way. The BJS therefore continues to devote its attention to such perspectives.