F2L, a peptide derived from heme-binding protein, chemoattracts mouse neutrophils by specifically activating Fpr2, the low-affinity N-formylpeptide receptor.
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 (EC(50) approximately 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 EC(50) values similar to those found for Fpr2-expressing cell lines ( approximately 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.
Gao
Ji-Liang
JL
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Guillabert
Aude
A
Hu
Jinyue
J
Le
Yingying
Y
Urizar
Eneko
E
Seligman
Eva
E
Fang
Kevin J
KJ
Yuan
Xiaoning
X
Imbault
Virginie
V
Communi
David
D
Wang
Ji Ming
JM
Parmentier
Marc
M
Murphy
Philip M
PM
Migeotte
Isabelle
I
D000818:Animals; D002118:Calcium; D002352:Carrier Proteins; D002630:Chemotactic Factors / Q000502:physiology*; D002633:Chemotaxis; D000081062:Heme-Binding Proteins; D006420:Hemeproteins; D006801:Humans; D051379:Mice; D009504:Neutrophils / Q000502:physiology*; D010455:Peptides; D044042:Receptors, Formyl Peptide / Q000378:metabolism*
D002352:Carrier Proteins; D002630:Chemotactic Factors; C498127:F2L peptide, human; C518154:F2L protein, mouse; D000081062:Heme-Binding Proteins; D006420:Hemeproteins; D010455:Peptides; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse; D002118:Calcium