Dynamic Instabilities Within Living Neutrophils

Abstract

The oscillatory metabolism of human neutrophils is used as a prototype biochemical subsystem to illustrate the ability of computational biology to both explain data and to predict biochemical mechanisms. Our work focuses upon the events surrounding neutrophil adherence and activation, which are features of many diseases. Cell activation is associated with increases in either or both the metabolic oscillatory frequency and amplitude. Our experimental studies and computational simulations have provided evidence that the frequency increase is linked to hexose monophosphate shunt (HMS) activation. Surprisingly, the increase in frequency is accounted for by a reduction in glycolytic activity. Increases in metabolic amplitude may also be observed during neutrophil activation and have been linked with the peroxidase cycle. Cell activation is independently regulated by these two pathways. The clinical relevance of this work is illustrated by frequency changes associated with febrile temperatures and diabetic levels of glucose. It is also demonstrated by neutrophil regulation during pregnancy, wherein high frequency oscillations are not observed and high amplitude oscillations are observed in the absence of cell activation stimuli. In this case, translocation of HMS enzymes to the centrosome accounts for the reduction in its activity, whereas translocation of myeloperoxidase (MPO) to the cell surface accounts for heightened peroxidase cycle activity during pregnancy. Hence, systems biology can be used to understand cell properties in complex clinical settings.