title: Glucose-6-phosphatase-β, implicated in a congenital neutropenia syndrome, is essential for macrophage energy homeostasis and functionality.
abstract: Glucose-6-phosphatase-β (G6Pase-β or G6PC3) deficiency, also known as severe congenital neutropenia syndrome 4, is characterized not only by neutropenia but also by impaired neutrophil energy homeostasis and functionality. We now show the syndrome is also associated with macrophage dysfunction, with murine G6pc3(-/-) macrophages having impairments in their respiratory burst, chemotaxis, calcium flux, and phagocytic activities. Consistent with a glucose-6-phosphate (G6P) metabolism deficiency, G6pc3(-/-) macrophages also have a lower glucose uptake and lower levels of G6P, lactate, and ATP than wild-type macrophages. Furthermore, the expression of NADPH oxidase subunits and membrane translocation of p47(phox) are down-regulated, and G6pc3(-/-) macrophages exhibit repressed trafficking in vivo both during an inflammatory response and in pregnancy. During pregnancy, the absence of G6Pase-β activity also leads to impaired energy homeostasis in the uterus and reduced fertility of G6pc3(-/-) mothers. Together these results show that immune deficiencies in this congenital neutropenia syndrome extend beyond neutrophil dysfunction.
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Hyun Sik
authors.initials: HS
authors.lastname: Jun
authors.forename: Yuk Yin
authors.initials: YY
authors.lastname: Cheung
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Lee
authors.forename: Brian C
authors.initials: BC
authors.lastname: Mansfield
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002633:Chemotaxis; D000080984:Congenital Bone Marrow Failure Syndromes; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000502:physiology*; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016897:Respiratory Burst; D015398:Signal Transduction; D013577:Syndrome
chemical_list: D016207:Cytokines; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; C495689:Slc2a3 protein, mouse; D019298:Glucose-6-Phosphate; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D005952:Glucose-6-Phosphatase; C519262:glucose-6-phosphatase-beta, mouse; D005947:Glucose; D002118:Calcium