Modeling neutrophil migration in dynamic chemoattractant gradients: assessing the role of exosomes during signal relay

Migrating cells often exhibit signal relay, a process in which cells migrating in response to a chemotactic gradient release a secondary chemoattractant to enhance directional migration. In neutrophils, signal relay toward the primary chemoattractant N-­formylmethionyl-leucyl-phenylalanine (fMLP) is mediated by leukotriene B(4) (LTB(4)). Recent evidence suggests that the release of LTB(4) from cells occurs through packaging in exosomes. Here we present a mathematical model of neutrophil signal relay that focuses on LTB(4) and its exosome-mediated secretion. We describe neutrophil chemotaxis in response to a combination of a defined gradient of fMLP and an evolving gradient of LTB(4), generated by cells in response to fMLP. Our model enables us to determine the gradient of LTB(4) arising either through directed secretion from cells or through time-varying release from exosomes. We predict that the secondary release of LTB(4) increases recruitment range and show that the exosomes provide a time delay mechanism that regulates the development of LTB(4) gradients. Additionally, we show that under decaying primary gradients, secondary gradients are more stable when secreted through exosomes as compared with direct secretion. Our chemotactic model, calibrated from observed responses of cells to gradients, thereby provides insight into chemotactic signal relay in neutrophils during inflammation.