Identification and characterization of an endogenous chemotactic ligand specific for FPRL2.
Chemotaxis of dendritic cells (DCs) and monocytes is a key step in the initiation of an adequate immune response. Formyl peptide receptor (FPR) and FPR-like receptor (FPRL)1, two G protein-coupled receptors belonging to the FPR family, play an essential role in host defense mechanisms against bacterial infection and in the regulation of inflammatory reactions. FPRL2, the third member of this structural family of chemoattractant receptors, is characterized by its specific expression on monocytes and DCs. Here, we present the isolation from a spleen extract and the functional characterization of F2L, a novel chemoattractant peptide acting specifically through FPRL2. F2L is an acetylated amino-terminal peptide derived from the cleavage of the human heme-binding protein, an intracellular tetrapyrolle-binding protein. The peptide binds and activates FPRL2 in the low nanomolar range, which triggers intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases through the G(i) class of heterotrimeric G proteins. When tested on monocytes and monocyte-derived DCs, F2L promotes calcium mobilization and chemotaxis. Therefore, F2L appears as a new natural chemoattractant peptide for DCs and monocytes, and the first potent and specific agonist of FPRL2.
Migeotte
Isabelle
I
Institut de Recherche en Biologie Humaine et Moléculaire, Université Libre de Bruxelles Campus Erasme, B-1070 Brussels, Belgium.
Riboldi
Elena
E
Franssen
Jean-Denis
JD
Grégoire
Françoise
F
Loison
Cécile
C
Wittamer
Valérie
V
Detheux
Michel
M
Robberecht
Patrick
P
Costagliola
Sabine
S
Vassart
Gilbert
G
Sozzani
Silvano
S
Parmentier
Marc
M
Communi
David
D
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002630:Chemotactic Factors / Q000235:genetics* / Q000378:metabolism; D002633:Chemotaxis / Q000235:genetics / Q000276:immunology*; D017931:DNA Primers; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D000081062:Heme-Binding Proteins; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010455:Peptides; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics*
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D002630:Chemotactic Factors; D017931:DNA Primers; C498127:F2L peptide, human; C105101:FPR2 protein, human; C469985:FPR3 protein, human; D000081062:Heme-Binding Proteins; D006420:Hemeproteins; D008024:Ligands; D010455:Peptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D002118:Calcium