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

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