title: Bone marrow-derived cells require a functional glucose 6-phosphate transporter for normal myeloid functions.
abstract: 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.
authors.affiliation: Section on Cellular Differentiation, Heritable Disorders Branch, NICHD, Molecular Signaling Section, Laboratory of Molecular Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: So Youn
authors.initials: SY
authors.lastname: Kim
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Nguyen
authors.forename: Ji-Liang
authors.initials: JL
authors.lastname: Gao
authors.forename: Philip M
authors.initials: PM
authors.lastname: Murphy
authors.forename: Brian C
authors.initials: BC
authors.lastname: Mansfield
authors.forename: Janice Yang
authors.initials: JY
authors.lastname: Chou
mesh_terms: 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
chemical_list: D017920:Antiporters; D001786:Blood Glucose; D018925:Chemokines; D009004:Monosaccharide Transport Proteins; C503532:Slc37a4 protein, mouse; D019298:Glucose-6-Phosphate