Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter.
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT-/-) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib. We demonstrate that the neutropenia is caused directly by the loss of G6PT activity; that chemotaxis and calcium flux, induced by the chemokines KC and macrophage inflammatory protein-2, are defective in G6PT-/- neutrophils; and that local production of these chemokines and the resultant neutrophil trafficking in vivo are depressed in G6PT-/- ascites during an inflammatory response. The bone and spleen of G6PT-/- mice are developmentally delayed and accompanied by marked hypocellularity of the bone marrow, elevation of myeloid progenitor cell frequencies in both organs and a corresponding dramatic increase in granulocyte colony stimulating factor levels in both GSD-Ib mice and humans. So, in addition to transient neutropenia, a sustained defect in neutrophil trafficking due to both the resistance of neutrophils to chemotactic factors, and reduced local production of neutrophil-specific chemokines at sites of inflammation, may underlie the myeloid deficiency in GSD-Ib. These findings demonstrate that G6PT is not just a G6P transport protein but also an important immunomodulatory protein whose activities need to be addressed in treating the myeloid complications in GSD-Ib patients.
Chen
Li-Yuan
LY
Section on Cellular Differentiation, Heritable Disorders Branch, Natioanl Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, USA.
Shieh
Jeng-Jer
JJ
Lin
Baochuan
B
Pan
Chi-Jiunn
CJ
Gao
Ji-Liang
JL
Murphy
Philip M
PM
Roe
Thomas F
TF
Moses
Shimon
S
Ward
Jerrold M
JM
Lee
Eric J
EJ
Westphal
Heiner
H
Mansfield
Brian C
BC
Chou
Janice Yang
JY
D000818:Animals; D017920:Antiporters / Q000172:deficiency*; D002118:Calcium / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D005808:Genes, Recessive; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism*; D005953:Glycogen Storage Disease Type I / Q000209:etiology / Q000473:pathology; D006706:Homeostasis; D007668:Kidney / Q000473:pathology; D007700:Kinetics; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000172:deficiency*; D009503:Neutropenia / Q000209:etiology / Q000503:physiopathology; D009504:Neutrophils / Q000378:metabolism*; D016897:Respiratory Burst; D015183:Restriction Mapping; D013997:Time Factors
D017920:Antiporters; D018925:Chemokines; D009004:Monosaccharide Transport Proteins; C503531:SLC37A4 protein, human; C503532:Slc37a4 protein, mouse; C111261:glucose 6-phosphate(transporter); D005947:Glucose; D002118:Calcium