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Originally published online as doi:10.1189/jlb.0908514 on May 4, 2009

Published online before print May 4, 2009
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(Journal of Leukocyte Biology. 2009;86:327-336.)
© 2009 Society for Leukocyte Biology

Interplay between signaling via the formyl peptide receptor (FPR) and chemokine receptor 3 (CCR3) in human eosinophils

Lena Svensson*,1, Elin Redvall*, Marianne Johnsson*, Anna-Lena Stenfeldt*, Claes Dahlgren{dagger} and Christine Wennerås*,{ddagger}

Departments of
* Clinical Bacteriology and
{dagger} Rheumatology and Inflammation Research, Göteborg University, Göteborg, Sweden; and
{ddagger} Department of Hematology and Coagulation, Sahlgrenska University Hospital, Göteborg, Sweden

1. Correspondence at current address: Leukocyte Adhesion Laboratory, Room 409, 44 Lincoln’s Inn Fields, London, WC2A 3Px, UK. E-mail: Lena.Svensson{at}cancer.org.uk

ABSTRACT

Eosinophils express the chemoattractant receptors CCR3 and FPR. CCR3 binds several agonists such as eotaxin-1, -2, and -3 and RANTES, whereas the FPR binds the formylated tripeptide fMLP and a host of other ligands. The aim of this study was to investigate if there is interplay between these two receptors regarding the elicitation of migration and respiratory burst in human blood-derived eosinophils. Inhibition of the FPR with the antagonists CyH and boc-MLP abrogated the migration of eosinophils toward all of the CCR3 agonists. Similar results were seen when the FPR was desensitized with its cognate ligand, fMLP. In contrast, the respiratory burst triggered by eotaxin-1 was not inhibited by CyH. Thus, signals evoked via the FPR caused unidirectional down-regulation of CCR3-mediated chemotaxis but not respiratory burst in human eosinophils. The underlying mechanism was neither reduced ability of the CCR3 ligand eotaxin-1 to bind to CCR3 nor down-regulation of CCR3 from the cell surface. Finally, confocal microscopy and adFRET analysis ruled out homo- or heterodimer formation between FPR and/or CCR3 as an explanation for the reduction in chemotaxis via CCR3. Pharmacologic inhibition of signal transduction molecules showed that the release of free oxygen radicals in response to eotaxin-1 compared with fMLP is relatively more dependent on the p38 MAPK pathway.

Key Words: respiratory burst • chemotaxis • eotaxin-1 (CCL11) • desensitization