Editors' ChoiceCell Migration

Keeping Neutrophils On Track

Sci. Signal.  22 May 2012:
Vol. 5, Issue 225, pp. ec141
DOI: 10.1126/scisignal.2003244

Neutrophils are the first responders to sites of infection and inflammation, and they are recruited from the blood by primary chemoattractants such as the bacterial formyl peptide fMLP. Exposure of cells at inflammatory sites to fMLP stimulates the release of secondary, proinflammatory chemoattractants, which recruit other cells and increase the inflammatory response. Noting that the secondary chemoattractant leukotriene B4 (LTB4), a metabolite of arachidonic acid (AA), is thought to be secreted by neutrophils upon reaching the site of inflammation, Afonso et al. investigated whether LTB4 might instead play a role during neutrophil migration. The authors confirmed that fMLP induced human neutrophils to secrete LTB4, and Western blotting analysis showed that pharmacological blocking of LTB4 production (by inhibiting an enzyme that metabolizes AA) or blocking the LTB4 receptor (BLT1) with an antagonist had no effect on fMLP-induced activation of the kinases ERK1/2 and Akt. However, LTB4 inhibition reduced the fMLP-dependent production of cAMP and phosphorylation of myosin II, which are required for neutrophil polarization and retraction of the back of the cell (uropod). At subsaturating concentrations of fMLP, LTB4 secretion enhanced actin polymerization at the leading edge of neutrophils and stabilized polarization. In a transwell assay, blocking LTB4 production or signaling inhibited migration of neutrophils to fMLP, but not to interleukin-8, a chemokine that induces comparatively little LTB4 secretion from neutrophils. Mouse neutrophils deficient in either BLT1 or an LTB4-generating enzyme migrated poorly to MKYMYm, a synthetic agonist of the fMLP receptor (FPR1). When mixed with wild-type neutrophils, fpr1–/– neutrophils gained the ability to migrate to MKYMYm; however, this was lost when the wild-type neutrophils were blocked from generating LTB4. Together, these data suggest that the secretion of LTB4 by neutrophils migrating to fMLP acts as a second gradient to increase selective fMLP-dependent signaling and enhance migration.

P. V. Afonso, M. Janka-Junttila, Y. J. Lee, C. P. McCann, C. M. Oliver, K. A. Aamer, W. Losert, M. T. Cicerone, C. A. Parent, LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev. Cell 22, 1079–1091 (2012). [PubMed]

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