Neutrophil stress and apoptosis underlie myeloid dysfunction in glycogen storage disease type Ib
Neutrophil stress and apoptosis underlie myeloid dysfunction in glycogen storage disease type Ib
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DOI：
10.1182/blood-2007-12-129114
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发表时间：
2008-06-15
期刊：
影响因子：
20.3
通讯作者：
Chou, Janice Y.
中科院分区：
文献类型：
--
作者：
Kim, So Youn;Jun, Hyun Sik;Chou, Janice Y.
糖原累积病Ib型（GSD-Ib）是由葡萄糖-6-磷酸（G6 P）转运蛋白（G6 PT）缺陷引起的，G6 PT与肝/肾/精氨酸限制性葡萄糖-6-磷酸酶-α（GVase-alpha）一起作用，以维持两餐之间的葡萄糖稳态。临床上，GSD-Ib患者表现出葡萄糖稳态紊乱和中性粒细胞功能障碍，但后者的原因尚不清楚。中性粒细胞表达普遍表达的G6 PT和G6 Pase-beta，它们一起将G6 P转运到内质网（ER）腔中并将其水解为葡萄糖。因为我们预期G6 PT缺陷的中性粒细胞不能产生内源性葡萄糖，我们假设这将导致ER应激和细胞凋亡增加。使用GSD-Ib小鼠，我们发现GSD-Ib中性粒细胞表现出ER分子伴侣和氧化应激的产生增加，与ER应激一致，以及膜联蛋白V结合和caspase-3活化增加，与凋亡率增加一致。Bax激活、促凋亡效应物的线粒体释放和半胱天冬酶-9激活证明了内在线粒体途径参与这些过程。结果表明，G6 P易位和水解所需的正常中性粒细胞功能和支持的假设，中性粒细胞功能障碍GSD-Ib是由于，至少部分是由于ER应激和细胞凋亡增加。
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that works with a liver/kidney/ intestine-restricted glucose-6-phosphatase-alpha (GVase-alpha) to maintain glucose homeostasis between meals. Clinically, GSD-Ib patients manifest disturbed glucose homeostasis and neutrophil dysfunctions but the cause of the latter is unclear. Neutrophils express the ubiquitously expressed G6PT and G6Pase-beta that together transport G6P into the endoplasmic reticulum (ER) lumen and hydrolyze it to glucose. Because we expected G6PT-deficient neutrophils to be unable to produce endogenous glucose, we hypothesized this would lead to ER stress and increased apoptosis. Using GSD-Ib mice, we showed that GSD-Ib neutrophils exhibited increased production of ER chaperones and oxidative stress, consistent with ER stress, and increased annexin V binding and caspase-3 activation, consistent with an increased rate of apoptosis. Bax activation, mitochondrial release of proapoptotic effectors, and caspase-9 activation demonstrated the involvement of the intrinsic mitochondrial pathway in these processes. The results demonstrate that G6P translocation and hydrolysis are required for normal neutrophil functions and support the hypothesis that neutrophil dysfunction in GSD-Ib is due, at least in part, to ER stress and increased apoptosis.