Elevated glucose concentrations promote receptor-independent activation of adherent human neutrophils: An experimental and computational approach

Ursula Kummer, Juergen Zobeley, Jens Christian Brasen, Ryan Fahmy, Andrei L. Kindzelskii, Aaron R. Petty, Andrea J. Clark, Howard R. Petty

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Neutrophil activation plays integral roles in host tissue damage and resistance to infectious diseases. As glucose uptake and NADPH availability are required for reactive oxygen metabolite production by neutrophils, we tested the hypothesis that pathological glucose levels (>= 12 mM) are sufficient to activate metabolism and reactive oxygen metabolite production in normal adherent neutrophils. We demonstrate that elevated glucose concentrations increase the neutrophil's metabolic oscillation frequency and hexose monophosphate shunt activity. In parallel, substantially increased rates of NO and superoxide formation were observed. However, these changes were not observed for sorbitol, a nonmetabolizable carbohydrate. Glucose transport appears to be important in this process as phloretin interferes with the glucose-specific receptor-independent activation of neutrophils. However, LY83583, an activator of glucose flux, promoted these changes at 1 mM glucose. The data suggest that at pathophysiologic concentrations, glucose uptake by mass action is sufficient to activate neutrophils, thus circumventing the normal receptor transduction mechanism. To enable us to mechanistically understand these dynamic metabolic changes, mathematical simulations were performed. A model for glycolysis in neutrophils was created. The results indicated that the frequency change in NAD(P)H oscillations can result from the activation of the hexose monophosphate shunt, which competes with glycolysis for glucose-6-phosphate. Experimental confirmation of these simulations was performed by measuring the effect of glucose concentrations on flavoprotein auto fluorescence, an indicator of the rate of mitochondrial electron transport. Moreover, after prolonged exposure to elevated glucose levels, neutrophils return to a "nonactivated'' phenotype and are refractile to immunologic stimulation. Our findings suggest that pathologic glucose levels promote the transient activation of neutrophils followed by the suppression of cell activity, which may contribute to nonspecific tissue damage and increased susceptibility to infections, respectively.
Original languageEnglish
JournalBiophysical Journal
Volume92
Issue number7
Pages (from-to)2597-2607
ISSN0006-3495
DOIs
Publication statusPublished - 2007
Externally publishedYes

Keywords

  • Biophysics
  • 6 anilino 5,8 quinolinequinone
  • carbohydrate
  • glucose
  • glucose 6 phosphate
  • hexose phosphate
  • nitric oxide
  • reduced nicotinamide adenine dinucleotide phosphate
  • sorbitol
  • superoxide
  • adult
  • article
  • autofluorescence
  • electron transport
  • glucose transport
  • glycolysis
  • human
  • human cell
  • human experiment
  • mathematical model
  • mitochondrion
  • neutrophil
  • normal human
  • oscillation
  • pathophysiology
  • Cell Adhesion
  • Cells, Cultured
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Glucose
  • Humans
  • Models, Cardiovascular
  • NADP
  • Neutrophil Activation
  • Neutrophils
  • Nitric Oxide
  • Oxygen
  • Reactive Oxygen Species
  • Receptors, Cell Surface
  • glucose receptor
  • 31C4KY9ESH Nitric Oxide
  • 53-59-8 NADP
  • IY9XDZ35W2 Glucose
  • S88TT14065 Oxygen
  • BIOPHYSICS
  • TYPE-2 DIABETIC-PATIENTS
  • SUPEROXIDE PRODUCTION
  • POLYMORPHONUCLEAR LEUKOCYTE
  • HYDROGEN-PEROXIDE
  • NADPH OXIDASE
  • NITRIC-OXIDE
  • CELL
  • OSCILLATIONS
  • METABOLISM
  • MELLITUS
  • hexose monophosphate shunt
  • metabolic oscillation frequency
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common
  • flavoprotein
  • glucose 58367-01-4 transport
  • glucose-6-phosphate 56-73-5
  • LY83583 91300-60-6
  • nitric oxide 10102-43-9
  • phloretin 60-82-2
  • sorbitol 50-70-4
  • superoxide 11062-77-4
  • 02506, Cytology - Animal
  • 02508, Cytology - Human
  • 10060, Biochemistry studies - General
  • 10068, Biochemistry studies - Carbohydrates
  • 13002, Metabolism - General metabolism and metabolic pathways
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 34502, Immunology - General and methods
  • Chemical Coordination and Homeostasis
  • Transport and Circulation
  • neutrophil immune system, blood and lymphatics
  • mathematical simulation mathematical and computer techniques
  • Biochemistry and Molecular Biophysics
  • Blood and Lymphatics
  • Immune System
  • Metabolism

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