Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib

Abstract

• A deficiency in G6PT impairs neutrophil energy homeostasis characterized by reduced intracellular levels of G6P, ATP, lactate, and NADPH. • Impaired energy homeostasis and activation of the HIF-1a/ PPAR-g pathway underlie neutrophil dysfunction in GSD-Ib.Glycogen storage disease type Ib (GSD-Ib) is an autosomal-recessive syndrome characterized by neutropenia and impaired glucose homeostasis resulting from a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT). The underlying cause of GSD-Ib neutropenia is an enhanced neutrophil apoptosis, but patients also manifest neutrophil dysfunction of unknown etiology. Previously, we showed G6PT interacts with the enzyme glucose-6-phosphatase-b (G6Pase-b) to regulate the availability of G6P/ glucose in neutrophils. A deficiency in G6Pase-b activity in neutrophils impairs both their energy homeostasis and function. We now show that G6PT-deficient neutrophils from GSD-Ib patients are similarly impaired. Their energy impairment is characterized by decreased glucose uptake and reduced levels of intracellular G6P, lactate, adenosine triphosphate, and reduced NAD phosphate, whereas functional impairment is reflected in reduced neutrophil respiratory burst, chemotaxis, and calcium mobilization. We further show that the mechanism of neutrophil dysfunction in GSD-Ib arises from activation of the hypoxia-inducible factor-1a/peroxisome-proliferators-activated receptor-g pathway.

Vitamin E Improves Clinical Outcome of Patients Affected by Glycogen Storage Disease Type Ib

“…GSD1b patients' neutropenia is caused by enhanced neutrophil ER stress, oxidative stress and apoptosis arising from loss of G6PT/G6Pase-b activity (Jun et al 2014). The G6P is the fuel for the pentose phosphate pathway that can generate NADPH by the hexose-6-phosphate dehydrogenase (Kim et al 2008).…”

“…G6PT interacts with the enzyme glucose-6-phosphatase-b (G6Pase-b) to regulate the availability of G6P/glucose in neutrophils (Guionie et al 2003;Jun et al 2014). A deficiency in G6PT in neutrophils impairs both their energy homeostasis and function.…”

Type I glycogen storage diseases: disorders of the glucose‐6‐phosphatase/glucose‐6‐phosphate transporter complexes

“…The latter pathway is mediated by the G6Pase-β/ G6PT complex . Both G6PT-deficient (Jun et al 2014) and G6Pase-β-deficient (Jun et al 2010) neutrophils exhibit impaired neutrophil glucose uptake. In parallel, levels of G6P, lactate, and ATP are markedly lower in G6PT-deficient (Jun et al 2014) and G6Pase-β-deficient neutrophils, compared with the controls.…”

Neutrophil Adhesion and Migration: Another Role of the Glucose-6-Phosphate Transporter

“…We have shown that G-CSF cannot correct impaired energy homeostasis in G6PT-deficient neutrophils in human GSD-Ib patients [5]. We recently showed that this growth factor also fails to rescue impaired neutrophil recruitment in G6pt -/-mice [9], highlighting the limitations of G-CSF in treating patients exhibiting neutrophil dysfunction.…”

“…Recently, we showed that G6PT-deficient neutrophils from GSD-Ib patients receiving granulocytecolony stimulating factor (G-CSF) therapy exhibited impaired energy homeostasis and function [5], suggesting that G6PT-regulated G6P metabolism is important for neutrophil function. However, G-CSF failed to correct impaired neutrophil energy homeostasis in GSD-Ib [5].…”