A Mathematical Model for Neutrophil Gradient Sensing and Polarization

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Abstract
Directed cell migration in response to chemical cues, also known as chemotaxis, is an important physiological process involved in wound healing, foraging, and the immune response. Cell migration requires the simultaneous formation of actin polymers at the leading edge and actomyosin complexes at the sides and back of the cell. An unresolved question in eukaryotic chemotaxis is how the same chemoattractant signal determines both the cell's front and back. Recent experimental studies have begun to reveal the biochemical mechanisms necessary for this polarized cellular response. We propose a mathematical model of neutrophil gradient sensing and polarization based on experimentally characterized biochemical mechanisms. The model demonstrates that the known dynamics for Rho GTPase and phosphatidylinositol-3-kinase (PI3K) activation are sufficient for both gradient sensing and polarization. In particular, the model demonstrates that these mechanisms can correctly localize the “front” and “rear” pathways in response to both uniform concentrations and gradients of chemical attractants, including in actin-inhibited cells. Furthermore, the model predictions are robust to the values of many parameters. A key result of the model is the proposed coincidence circuit involving PI3K and Ras that obviates the need for the “global inhibitors” proposed, though never experimentally verified, in many previous mathematical models of eukaryotic chemotaxis. Finally, experiments are proposed to (in)validate this model and further our understanding of neutrophil chemotaxis. Neutrophils target sites of infection and inflammation by sensing chemical signals produced by damaged tissue and infecting microbes and then move in the direction where their concentration is greatest. An open question is how neutrophils integrate this information to determine the direction of motility. We present a mathematical model for the intracellular signaling network regulating polarization and chemotaxis in neutrophils. We demonstrate how the activation of two antagonizing pathways robustly establishes the front and back of the migrating cell. The model is able to reproduce a number of experimental studies, and new experiments are proposed to test different aspects of the model. A key result is the characterization of a coincidence circuit involving phosphatidylinositol-3-kinase (PI3K) and Ras. We demonstrate that this circuit plays a critical role in selectively localizing F-actin to the front of the cell and actomyosin complexes to the rear. As directed motility in response to chemical cues is critical in a number of processes including wound healing and tumor metastasis, the results and insights gained from the model may be applicable to other cell types and organisms.