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F2L, a Peptide Derived from Heme-Binding Protein, Chemoattracts Mouse Neutrophils by Specifically Activating Fpr2, the Low-Affinity N-Formylpeptide Receptor¹

Ji-Liang Gao^2,*, Aude Guillabert^2,, Jinyue Hu, Yingying Le, Eneko Urizar, Eva Seligman^*, Kevin J. Fang^*, Xiaoning Yuan^*, Virginie Imbault, David Communi, Ji Ming Wang, Marc Parmentier, Philip M. Murphy^3,* and Isabelle Migeotte^3,

^* Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles Campus Erasme, Brussels, Belgium; and Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702

F2L (formylpeptide receptor (FPR)-like (FPRL)-2 ligand), a highly conserved acetylated peptide derived from the amino-terminal cleavage of heme-binding protein, is a potent chemoattractant for human monocytes and dendritic cells, and inhibits LPS-induced human dendritic cell maturation. We recently reported that F2L is able to activate the human receptors FPRL-1 and FPRL2, two members of the FPR family, with highest selectivity and affinity for FPRL2. To facilitate delineation of mechanisms of F2L action in vivo, we have now attempted to define its mouse receptors. This is complicated by the nonequivalence of the human and mouse FPR gene families (three vs at least eight members, respectively). When cell lines were transfected with plasmids encoding the eight mouse receptors, only the one expressing the receptor Fpr2 responded to F2L (EC₅₀ 400 nM for both human and mouse F2L in both calcium flux and cAMP inhibition assays). This value is similar to F2L potency at human FPRL1. Consistent with this, mouse neutrophils, which like macrophages and dendritic cells express Fpr2, responded to human and mouse F2L in both calcium flux and chemotaxis assays with EC₅₀ values similar to those found for Fpr2-expressing cell lines (500 nM). Moreover, neutrophils from mice genetically deficient in Fpr2 failed to respond to F2L. Thus, Fpr2 is a mouse receptor for F2L, and can be targeted for the study of F2L action in mouse models.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister’s Office, Science Policy Programming, the LifeSciHealth Programme of the European Community (Grants LSHB-CT-2003-503337, GPCRs, and LSHB-CT-2005-518167, INNOCHEM), the Fonds de la Recherche Scientifique Médicale of Belgium, and the Fondation Médicale Reine Elisabeth (to M.P.). The scientific responsibility is assumed by the authors. I.M. was Aspirant, and D.C. is Research Associate of the Belgian Fonds National de la Recherche Scientifique. A.G. was supported by the Université Libre de Bruxelles. E.U. was financed by a grant from the Basque country government.

² J.-L.G. and A.G. contributed equally to this work.

³ Address correspondence and reprint requests Dr. Philip M. Murphy, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; E-mail address: pmm{at}nih.gov or Dr. Isabelle Migeotte, 808 route de Lennik, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles Campus Erasme, B-1070 Brussels, Belgium; E-mail address: migeotti{at}mskcc.org

⁴ Abbreviations used in this paper: FPR, formylpeptide receptor; FPR, FPRL, F2L, FPR-like ligand; HBP, heme-binding protein; wt, wild type; ko, knockout; FSK, forskolin.

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