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Directional decisions during neutrophil chemotaxis inside bifurcating channels.

ABSTRACT: The directional migration of human neutrophils in classical chemotaxis assays is often described as a "biased random walk" implying significant randomness in speed and directionality. However, these experiments are inconsistent with in vivo observations, where neutrophils can navigate effectively through complex tissue microenvironments towards their targets. Here, we demonstrate a novel biomimetic assay for neutrophil chemotaxis using enclosed microfluidic channels. Remarkably, under these enclosed conditions, neutrophils recapitulate the highly robust and efficient navigation observed in vivo. In straight channels, neutrophils undergo sustained, unidirectional motion towards a chemoattractant source. In more complex maze-like geometries, neutrophils are able to select the most direct route over 90% of the time. Finally, at symmetric bifurcations, neutrophils split their leading edge into two sections and a "tug of war" ensues. The competition between the two new leading edges is ultimately resolved by stochastic, symmetry-breaking behavior. This behavior is suggestive of directional decision-making localized at the leading edge and a signaling role played by the cellular cytoskeleton.

SUBMITTER: Ambravaneswaran V

PROVIDER: S-EPMC3001269 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Directional decisions during neutrophil chemotaxis inside bifurcating channels.

Ambravaneswaran Vijayakrishnan V Wong Ian Y IY Aranyosi Alexander J AJ Toner Mehmet M Irimia Daniel D

Integrative biology : quantitative biosciences from nano to macro 20100802 11-12

The directional migration of human neutrophils in classical chemotaxis assays is often described as a "biased random walk" implying significant randomness in speed and directionality. However, these experiments are inconsistent with in vivo observations, where neutrophils can navigate effectively through complex tissue microenvironments towards their targets. Here, we demonstrate a novel biomimetic assay for neutrophil chemotaxis using enclosed microfluidic channels. Remarkably, under these encl ...[more]

PMID: 20676444

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Project description:Neutrophils are always surrounded by/interacting with other components of the immune system; however, the current mechanistic understanding of neutrophil function is largely based on how neutrophils respond to a single chemical signal in a simplified environment. Such approaches are unable to recapitulate the in vivo microenvironment; thus, cell behavior may not fully represent the physiological behavior. Herein, we exploit a microfluidic model of the complex in vivo milieu to investigate how cell-cell interactions influence human neutrophil migration and surface marker expression. Neutrophil migration against a bacterially derived chemoattractant (formyl-met-leu-phe, fMLP), with and without preactivation by interleukins (interleukin-2 or interleukin-6), was evaluated in the presence and absence of endothelial support cells. Preactivation by interleukins or interaction with endothelial cells resulted in altered migration rates compared to naïve neutrophils, and migration trajectories deviated from the expected movement toward the fMLP signal. Interestingly, interaction with both interleukins and endothelial cells simultaneously resulted in a slight compensation in the deviation-on endothelial cells, 34.4% of untreated neutrophils moved away from the fMLP signal, while only 15.2 or 22.2% (interleukin-2-or interleukin-6-activated) of preactivated cells moved away from fMLP. Neutrophils interacting with interleukins and/or endothelial cells were still capable of prioritizing the fMLP signal over a competing chemoattractant, leukotriene B4 (LTB4). Fluorescence imaging of individual human neutrophils revealed that neutrophils treated with endothelial-cell-conditioned media showed up-regulation of the surface adhesion molecules cluster determinant 11b and 66b (CD11b and CD66b) upon stimulation. On the other hand, CD11b and CD66b down-regulation was observed in untreated neutrophils. These results leverage single cell analysis to reveal that the interaction between neutrophils and endothelial cells is involved in surface marker regulation and thus chemotaxis of neutrophils. This study brings new knowledge about neutrophil chemotaxis in the context of cell-to-cell communications, yielding both fundamental and therapeutically relevant insight.

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Directional decisions during neutrophil chemotaxis inside bifurcating channels.

Publications

Directional decisions during neutrophil chemotaxis inside bifurcating channels.

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