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

ABSTRACT: 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 B₄ (LTB₄). Recent evidence suggests that the release of LTB₄ from cells occurs through packaging in exosomes. Here we present a mathematical model of neutrophil signal relay that focuses on LTB₄ 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 LTB₄, generated by cells in response to fMLP. Our model enables us to determine the gradient of LTB₄ arising either through directed secretion from cells or through time-varying release from exosomes. We predict that the secondary release of LTB₄ increases recruitment range and show that the exosomes provide a time delay mechanism that regulates the development of LTB₄ 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.

SUBMITTER: Szatmary AC

PROVIDER: S-EPMC5687044 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Szatmary Alex C AC Nossal Ralph R Parent Carole A CA Majumdar Ritankar R

Molecular biology of the cell 20170927 23

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 B4 (LTB4). Recent evidence suggests that the release of LTB4 from cells occurs through packaging in exosomes. Here we present a mathematical m ...[more]

PMID: 28954858

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Project description:Electric fields are generated in vivo in a variety of physiologic and pathologic settings, including wound healing and immune response to injuries to epithelial barriers (e.g. lung pneumocytes). Immune cells are known to migrate towards both chemical (chemotaxis), physical (mechanotaxis) and electric stimuli (electrotaxis). Electrotaxis is the guided migration of cells along electric fields, and has previously been reported in T-cells and cancer cells. However, there remains a need for engineering tools with high spatial and temporal resolution to quantify EF guided migration. Here we report the development of an electrotaxis-on-chip (ETOC) platform that enables the quantification of dHL-60 cell, a model neutrophil-like cell line, migration toward both electrical and chemoattractant gradients. Neutrophils are the most abundant white blood cells and set the stage for the magnitude of the immune response. Therefore, developing engineering tools to direct neutrophil migration patterns has applications in both infectious disease and inflammatory disorders. The ETOC developed in this study has embedded electrodes and four migration zones connected to a central cell-loading chamber with migration channels [10 µm X 10 µm]. This device enables both parallel and competing chemoattractant and electric fields. We use our novel ETOC platform to investigate dHL-60 cell migration in three biologically relevant conditions: 1) in a DC electric field; 2) parallel chemical gradient and electric fields; and 3) perpendicular chemical gradient and electric field. In this study we used differentiated leukemia cancer cells (dHL60 cells), an accepted model for human peripheral blood neutrophils. We first quantified effects of electric field intensities (0.4V/cm-1V/cm) on dHL-60 cell electrotaxis. Our results show optimal migration at 0.6 V/cm. In the second scenario, we tested whether it was possible to increase dHL-60 cell migration to a bacterial signal [N-formylated peptides (fMLP)] by adding a parallel electric field. Our results show that there was significant increase (6-fold increase) in dHL60 migration toward fMLP and cathode of DC electric field (0.6V/cm, n=4, p-value<0.005) vs. fMLP alone. Finally, we evaluated whether we could decrease or re-direct dHL-60 cell migration away from an inflammatory signal [leukotriene B4 (LTB4)]. The perpendicular electric field significantly decreased migration (2.9-fold decrease) of dHL60s toward LTB4 vs. LTB4 alone. Our microfluidic device enabled us to quantify single-cell electrotaxis velocity (7.9 µm/min ± 3.6). The magnitude and direction of the electric field can be more precisely and quickly changed than most other guidance cues such as chemical cues in clinical investigation. A better understanding of EF guided cell migration will enable the development of new EF-based treatments to precisely direct immune cell migration for wound care, infection, and other inflammatory disorders.

Dataset Information

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

Publications

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

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