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Published on: September 20, 2011
Chemoattractant concentration-dependent tuning of ERK signaling dynamics in migrating neutrophils
Elizabeth R Zhang1,2, Shanshan Liu1,2, Lani F Wu2,3
1Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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.
Insights
Neutrophils migrate directionally towards bacterial peptides at low concentrations but become circuitous at high concentrations. Extracellular signal-regulated kinase (ERK) pathway dynamics, specifically its graded activation, are crucial for this neutrophil migration behavior.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Neutrophil chemotaxis is vital for immune defense against bacterial infections.
- Neutrophils exhibit distinct migration patterns (directional vs. circuitous) based on bacterial peptide (fMLP) concentration.
- The extracellular signal-regulated kinase (ERK) pathway is involved in regulating these concentration-dependent migration modes.
Purpose of the Study:
- To investigate the role and regulation of ERK signaling in neutrophil migration.
- To analyze single-cell migration dynamics in response to varying fMLP concentrations over time.
- To elucidate the relationship between ERK activation patterns and neutrophil migration behavior.
Main Methods:
- Single-cell analysis of neutrophil migration.
- Exposure of neutrophils to different concentrations of fMLP over time.
- Investigation of ERK and p38 pathway activation and inhibition.
Main Results:
- ERK activation demonstrated a graded response to fMLP concentration, peaking around 100 nM fMLP.
- ERK inactivation was promoted by the p38 pathway.
- Neutrophil directional migration was maximal at approximately 100 nM fMLP and required ERK signaling, but not p38.
Conclusions:
- ERK signaling exhibits graded activation and p38-dependent inhibition in chemotactic neutrophils.
- These specific ERK dynamics are essential for promoting neutrophil migration towards fMLP gradients.
- The study clarifies the intricate mechanisms governing neutrophil chemotaxis and immune responses.
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