Bone marrow-derived cells require a functional glucose 6-phosphate transporter for normal myeloid functions.
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the ubiquitously expressed glucose 6-phosphate transporter (Glc-6-PT). Glc-6-PT activity has been shown to be critical in the liver and kidney where a deficiency disrupts glucose homeostasis. GSD-Ib patients also have defects in the neutrophil respiratory burst, chemotaxis, and calcium flux. They also manifest neutropenia, but whether Glc-6-PT deficiency in the bone marrow underlies myeloid dysfunctions in GSD-Ib remains controversial. To address this, we transferred bone marrow from Glc-6-PT-deficient (Glc-6-PT(-/-)) mice to wild-type mice to generate chimeric mice (BM-Glc-6-PT(-/-)). As a control, we also transferred bone marrow between wild-type mice (BM-Glc-6-PT(+/+)). While BM-Glc-6-PT(+/+) mice have normal myeloid functions, BM-Glc-6-PT(-/-) mice manifest myeloid abnormalities characteristic of Glc-6-PT(-/-) mice. Both have impairments in their neutrophil respiratory burst, chemotaxis response, and calcium flux activities and exhibit neutropenia. In the bone marrow of BM-Glc-6-PT(-/-) and Glc-6-PT(-/-) mice, the numbers of myeloid progenitor cells are increased, while in the serum there is an increase in granulocyte colony-stimulating factor and chemokine KC levels. Moreover, in an experimental model of peritoneal inflammation, local production of KC and the related chemokine macrophage inflammatory protein-2 is decreased in both BM-Glc-6-PT(-/-) and Glc-6-PT(-/-) mice along with depressed peritoneal neutrophil accumulation. The neutrophil recruitment defect was less severe in BM-Glc-6-PT(-/-) mice than in Glc-6-PT(-/-) mice. These findings demonstrate that Glc-6-PT expression in bone marrow and neutrophils is required for normal myeloid functions and that non-marrow Glc-6-PT activity also influences some myeloid functions.
Kim
So Youn
SY
Section on Cellular Differentiation, Heritable Disorders Branch, NICHD, Molecular Signaling Section, Laboratory of Molecular Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nguyen
Andrew D
AD
Gao
Ji-Liang
JL
Murphy
Philip M
PM
Mansfield
Brian C
BC
Chou
Janice Yang
JY
D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000502:physiology*; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000502:physiology*; D022423:Myeloid Cells / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism
D017920:Antiporters; D001786:Blood Glucose; D018925:Chemokines; D009004:Monosaccharide Transport Proteins; C503532:Slc37a4 protein, mouse; D019298:Glucose-6-Phosphate