Leukotriene B4 autocrine/paracrine secretion amplifies fMLP-gradient sensing during neutrophil chemotaxis

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NCI	IMMUNO/INFLAM-1

* FARE Award Winner

Authors

• PV Afonso
• M Janka-Juntilla
• CM Oliver
• CP McCann
• CA Parent

Abstract

In response to the bacterial peptide fMLP, neutrophils secrete the secondary chemoattractant leukotriene B4 (LTB4). This potent molecule is known to be secreted at inflammation sites in vivo and enhance neutrophil recruitment. We hypothesize that LTB4 is also secreted while cells migrate; in this study, we analyzed the impact of LTB4 secretion on collective neutrophil chemotaxis towards fMLP. For this purpose, we addressed the effect of drugs that block LTB4 signaling on primary human neutrophil activation and chemotaxis. We find that LTB4 production is important for intracellular cAMP accumulation, actin polymerization and cell polarization when cells are stimulated with a low concentration of fMLP. We also show that the inhibition of LTB4 relay inhibits chemotaxis to fMLP; this inhibition is stronger when cells migrate towards lower concentration of fMLP. Finally, we demonstrate that neutrophils isolated from mice lacking the fMLP receptor 1 (FPR1) can migrate to fMLP when mixed with neutrophils isolated from WT mice. Furthermore, blocking LTB4 production in WT neutrophils abolishes recruitment of FPR1-/- neutrophils. This study demonstrates that LTB4 secreted by neutrophils forms a secondary gradient that significantly amplifies neutrophil migration to primary chemoattractants by selectively controlling signaling cascades.

back to top