title: Metabolic adaptation of neutrophils in cystic fibrosis airways involves distinct shifts in nutrient transporter expression.
abstract: Inflammatory conditions can profoundly alter human neutrophils, a leukocyte subset generally viewed as terminally differentiated and catabolic. In cystic fibrosis (CF) patients, neutrophils recruited to CF airways show active exocytosis and sustained phosphorylation of prosurvival, metabolic pathways. Because the CF airway lumen is also characterized by high levels of free glucose and amino acids, we compared surface expression of Glut1 (glucose) and ASCT2 (neutral amino acids) transporters, as well as that of PiT1 and PiT2 (inorganic phosphate transporters), in blood and airway neutrophils, using specific retroviral envelope-derived ligands. Neither nutrient transporter expression nor glucose uptake was altered on blood neutrophils from CF patients compared with healthy controls. Notably, however, airway neutrophils of CF patients had higher levels of PiT1 and Glut1 and increased glucose uptake compared with their blood counterparts. Based on primary granule exocytosis and scatter profiles, CF airway neutrophils could be divided into two subsets, with one of the subsets characterized by more salient increases in Glut1, ASCT2, PiT1, and PiT2 expression. Moreover, in vitro exocytosis assays of blood neutrophils suggest that surface nutrient transporter expression is not directly associated with primary (or secondary) granule exocytosis. Although expression of nutrient transporters on CF blood or airway neutrophils was not altered by genotype, age, gender, or Pseudomonas aeruginosa infection, oral steroid treatment decreased Glut1 and PiT2 levels in blood neutrophils. Thus, neutrophils recruited from blood into the CF airway lumen display augmented cell surface nutrient transporter expression and glucose uptake, consistent with metabolic adaptation.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, GA 30322, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Laval
authors.forename: Jawida
authors.initials: J
authors.lastname: Touhami
authors.forename: Leonore A
authors.initials: LA
authors.lastname: Herzenberg
authors.forename: Carol
authors.initials: C
authors.lastname: Conrad
authors.forename: Naomi
authors.initials: N
authors.lastname: Taylor
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Battini
authors.forename: Marc
authors.initials: M
authors.lastname: Sitbon
authors.forename: Rabindra
authors.initials: R
authors.lastname: Tirouvanziam
mesh_terms: D026962:Amino Acid Transport System ASC / Q000378:metabolism; D003550:Cystic Fibrosis / Q000276:immunology* / Q000378:metabolism*; D005434:Flow Cytometry; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism
chemical_list: D026962:Amino Acid Transport System ASC; D051272:Glucose Transporter Type 1; D026901:Membrane Transport Proteins; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human; C493586:SLC20A1 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III