Dougher Christopher W L, Buffone Alexander, Nemeth Michael J, Nasirikenari Mehrab, Irons Eric E, Bogner Paul N, Lau Joseph T Y
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA; and.
J Leukoc Biol. 2017 Aug;102(2):507-516. doi: 10.1189/jlb.3A1216-538RR. Epub 2017 May 26.
Responding to systemic demands in producing and replenishing end-effector blood cells is predicated on the appropriate delivery and interpretation of extrinsic signals to the HSPCs. The data presented herein implicate the systemic, extracellular form of the glycosyltransferase ST6Gal-1 in the regulation of late-stage neutrophil development. ST6Gal-1 is typically a membrane-bound enzyme sequestered within the intracellular secretory apparatus, but an extracellular form is released into the blood from the liver. Both human and murine HSPCs, upon exposure to extracellular ST6Gal-1 ex vivo, exhibited decreased proliferation, diminished expression of the neutrophilic primary granule protein MPO, and decreased appearance of CD11b cells. HSPC suppression was preceded by decreased STAT-3 phosphorylation and diminished C/EBPα expression, without increased apoptosis, indicating attenuated G-CSF receptor signaling. A murine model to raise systemic ST6Gal-1 level was developed to examine the role of the circulatory enzyme in vivo. Our results show that systemic ST6Gal-1 modified the cell surface of the GMP subset of HSPCs and decreased marrow neutrophil reserves. Acute airway neutrophilic inflammation by LPS challenge was used to drive demand for new neutrophil production. Reduced neutrophil infiltration into the airway was observed in mice with elevated circulatory ST6Gal-1 levels. The blunted transition of GMPs into GPs in vitro is consistent with ST6Gal-1-attenuated granulopoiesis. The data confirm that circulatory ST6Gal-1 is a negative systemic regulator of granulopoiesis and moreover suggest a clinical potential to limit the number of inflammatory cells by manipulating blood ST6Gal-1 levels.
对产生和补充终末效应血细胞的全身需求的响应，取决于向造血干细胞（HSPCs）适当传递和解读外在信号。本文所呈现的数据表明，糖基转移酶ST6Gal-1的全身细胞外形式参与晚期中性粒细胞发育的调控。ST6Gal-1通常是一种隔离于细胞内分泌装置内的膜结合酶，但一种细胞外形式会从肝脏释放到血液中。人源和鼠源HSPCs在体外暴露于细胞外ST6Gal-1后，均表现出增殖减少、嗜中性初级颗粒蛋白MPO的表达降低以及CD11b细胞出现减少。HSPCs的抑制在STAT-3磷酸化降低和C/EBPα表达减少之前出现，且未伴有细胞凋亡增加，表明G-CSF受体信号减弱。构建了一个提高全身ST6Gal-1水平的鼠模型，以研究循环酶在体内的作用。我们的结果表明，全身ST6Gal-1改变了HSPCs中粒细胞-巨噬细胞集落形成单位（GMP）亚群的细胞表面，并减少了骨髓中性粒细胞储备。通过脂多糖（LPS）刺激引发急性气道嗜中性炎症，以驱动对新的中性粒细胞产生的需求。在循环ST6Gal-1水平升高的小鼠中，观察到气道嗜中性粒细胞浸润减少。体外GMPs向粒细胞前体细胞（GPs）的钝化转变与ST6Gal-1减弱的粒细胞生成一致。数据证实循环ST6Gal-1是粒细胞生成的负性全身调节因子，此外还表明通过操纵血液中ST6Gal-1水平来限制炎症细胞数量具有临床潜力。
