Research ArticleCell Migration

Chemoattractant concentration–dependent tuning of ERK signaling dynamics in migrating neutrophils

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Sci. Signal.  13 Dec 2016:
Vol. 9, Issue 458, pp. ra122
DOI: 10.1126/scisignal.aag0486

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Tuning the ERK migration engine

The chemotaxis of neutrophils toward the source of the bacterial peptide fMLP is critical for the early immune response to infection. As they travel up a concentration gradient of fMLP, neutrophils switch from exhibiting directed migration to showing a circuitous movement. Zhang et al. used video microscopy to monitor neutrophil migration along a gradient of fluorescent fMLP and found that the switch in migration modes occurred at about 100 nM fMLP. This was also the position in the gradient at which the kinase ERK, which up to this point drove migration, became inhibited. Furthermore, this concentration of fMLP stimulated the activity of the kinase p38, which in turn inhibited ERK activity. Together, these data suggest that the fMLP concentration–dependent interplay between ERK and p38 activities controls neutrophil migration.

Abstract

The directed migration (chemotaxis) of neutrophils toward the bacterial peptide N-formyl-Met-Leu-Phe (fMLP) is a crucial process in immune defense against invading bacteria. While navigating through a gradient of increasing concentrations of fMLP, neutrophils and neutrophil-like HL-60 cells switch from exhibiting directional migration at low fMLP concentrations to exhibiting circuitous migration at high fMLP concentrations. The extracellular signal–regulated kinase (ERK) pathway is implicated in balancing this fMLP concentration–dependent switch in migration modes. We investigated the role and regulation of ERK signaling through single-cell analysis of neutrophil migration in response to different fMLP concentrations over time. We found that ERK exhibited gradated, rather than all-or-none, responses to fMLP concentration. Maximal ERK activation occurred in response to about 100 nM fMLP, and ERK inactivation was promoted by p38. Furthermore, we found that directional migration of neutrophils reached a maximal extent at about 100 nM fMLP and that ERK, but not p38, was required for neutrophil migration. Thus, our data suggest that, in chemotactic neutrophils responding to fMLP, ERK displays gradated activation and p38-dependent inhibition and that these ERK dynamics promote neutrophil migration.

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