title: Glycogen storage disease type Ib neutrophils exhibit impaired cell adhesion and migration.
abstract: Glycogen storage disease type Ib (GSD-Ib), characterized by impaired glucose homeostasis, neutropenia, and neutrophil dysfunction, is an inherited autosomal recessive disorder caused by a deficiency in the glucose-6-phosphate transporter (G6PT). Neutrophils play an essential role in the defense against invading pathogens. The recruitment of neutrophils towards the inflammation sites in response to inflammatory stimuli is a tightly regulated process involving rolling, adhesion, and transmigration. In this study, we investigated the role of G6PT in neutrophil adhesion and migration using in vivo and in vitro models. We showed that the GSD-Ib (G6pt-/-) mice manifested severe neutropenia in both blood and bone marrow, and treating G6pt-/-mice with granulocyte colony-stimulating factor (G-CSF) corrected neutropenia. However, upon thioglycolate challenge, neutrophils from both untreated and G-CSF-treated G6pt-/-mice exhibited decreased ability to migrate to the peritoneal cavity. In vitro migration and cell adhesion of G6PT-deficient neutrophils were also significantly impaired. Defects in cell migration were not due to enhanced apoptosis or altered fMLP receptor expression. Remarkably, the expression of the β2 integrins CD11a and CD11b, which are critical for cell adhesion, was greatly decreased in G6PT-deficient neutrophils. This study suggests that deficiencies in G6PT cause impairment in neutrophil adhesion and migration via aberrant expression of β2 integrins, and our finding should facilitate the development of novel therapies for GSD-Ib.
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Goo-Young
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Joon Hyun
authors.initials: JH
authors.lastname: Kwon
authors.affiliation: Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, Sejong 339-700, Republic of Korea. Electronic address: toddjun@korea.ac.kr.
authors.forename: Hyun Sik
authors.initials: HS
authors.lastname: Jun
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: chouja@mail.nih.gov.
authors.forename: Janice
authors.initials: J
authors.lastname: Chou
mesh_terms: D000818:Animals; D017920:Antiporters / Q000235:genetics; D017209:Apoptosis; D018938:Caco-2 Cells; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D017353:Gene Deletion; D005953:Glycogen Storage Disease Type I / Q000150:complications / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009503:Neutropenia / Q000150:complications / Q000235:genetics / Q000473:pathology*; D009504:Neutrophils / Q000166:cytology / Q000473:pathology*
chemical_list: D017920:Antiporters; D009004:Monosaccharide Transport Proteins; C111261:glucose 6-phosphate(transporter)
keywords: CD11a; CD11b; Glucose-6-phosphate transporter; Migration; Neutrophil adhesion