Survey
Formyl peptide receptors: A promiscuous subfamily of G protein-coupled receptors controlling immune responses

https://doi.org/10.1016/j.cytogfr.2006.09.009Get rights and content

Abstract

The formyl peptide receptor (FPR) family is involved in host defence against pathogens, but also in sensing internal molecules that may constitute signals of cellular dysfunction. It includes three subtypes in human and other primates. FPR responds to formyl peptides derived from bacterial and mitochondrial proteins. FPRL1 displays a large array of exogenous and endogenous ligands, including the chemokine variant sCKβ8-1, the neuroprotective peptide humanin, and lipoxin A4. Two high affinity agonists (F2L and humanin) were recently described for FPRL2. In mouse, eight FPR-related receptors have been described. Fpr1 is the ortholog of human FPR, while fpr2 appears to share many ligands with human FPRL1. Altogether, the physiological role of the FPR family is still incompletely understood, due in part to the large variety of ligands, the redundancy with other chemoattractant agents, and the lack of clear orthologs between human and mouse receptors. Newly developed tools will allow to study further this family of receptors.

Section snippets

Leukocyte chemoattractant agents

Leukocyte trafficking across the body is controlled by a variety of protein families that include integrins, cell adhesion molecules of the immunoglobulin family, selectins and glycoprotein selectin ligands, as well as a diverse group of chemoattractant molecules. Chemoattractants are responsible for the directional movement of the various leukocyte populations to specific compartments of the body, including primary and secondary lymphoid organs, tissues involved in immune surveillance (skin,

Discovery and cloning of human formyl peptide receptors

The human formyl peptide receptor (FPR) was defined pharmacologically in 1976 as a high affinity binding site, on the surface of neutrophils, for the peptide N-formyl-methionine-leucine-phenylalanine (fMLF), the prototype for N-formylated bacterial peptides [1]. This receptor was later cloned in 1990 by functional screening of a cDNA library constructed from differentiated HL-60 myeloid leukaemia cells. The cDNA encoded a protein of 350 amino acids [2]. The formyl peptide receptor gene spans 6 

Genetic variants and mammalian orthologs of formyl peptide receptors

In human, single nucleotide polymorphisms in the FPR coding region have been reported, and two of these variants, which encode dysfunctional alleles, have been associated with juvenile periodontitis, as the result of an increased susceptibility to infection by Actinobacillus actinomycetescomitans [9], [10].

The FPR genes of non human primates are 95–99% identical to their human ortholog, and the highest divergence resides in the extracellular loops, which are presumably involved in ligand

Tissue and cellular distribution of receptors of the FPR family

FPR expression has initially been described in phagocytic leukocytes, monocytes and neutrophils (Table 1). It was later observed in immature dendritic cells (DCs), microglial cells, platelets, spleen and bone marrow. It is also described in non-hematopoietic cell populations and tissues, such as hepatocytes, fibroblasts, astrocytes, neurons of the autonomic nervous system, lung and lung carcinoma cells, thyroid, adrenals, heart, the tunica media of coronary arteries, uterus, ovary, placenta,

Signal transduction of formyl peptide receptors

Signal transduction pathways activated by formyl peptide receptors are reviewed in detail elsewhere [33]. The pattern of ligand recognition and activation of FPR and FPRL1 in neutrophils has also been recently reviewed [34]. FPR, FPRL1 and FPRL2 are all coupled to the Gi family of G proteins, as indicated by the total loss of cell response to their respective agonists, upon exposure to Pertussis toxin [1], [20], [35]. More specifically, FPR is coupled to Gi1, Gi2 and Gi3, but coupling to G0, Gz

Formyl peptides

The first described ligand of FPR is the prototypical formylated peptide fMLF from Escherichia coli, which binds and activates FPR with high affinity (Table 2). Peptides derived from Listeria monocytogenes were also shown to selectively activate FPR. They display a very weak activity on FPRL1, and none on FPRL2 [47]. The formyl group has been shown to be necessary for activation by the tripeptide, but it was later shown that unformylated but longer peptides were also able to activate phagocytes

Pharmacology and putative functions of FPRL1

FPRL1 is an exceptionally promiscuous receptor, responding to numerous ligands of different origins and of high structural diversity [1], [20]. FPRL1 was initially defined as a low affinity receptor for fMLF, with an affinity around 1 μM [4]. Thereafter, a number of additional ligands were described over the years.

Synthetic peptides

The first molecules proposed as FPRL2 agonists were the synthetic W peptides active on FPR and FPRL1 [35]. On FPRL2-expressing HL-60 cells, WKYMVM and WKYMVm elicited calcium mobilisation and chemotaxis. In a competition binding assay performed on FPRL2-expressing RINm5F cells, WKYMVm and WKYMVM competed for the tracer (125I-WKYMVm) with an IC50 of about 3 μM. Phosphorylation of the receptor in RINm5F cells was detected at rest, and slightly increased following incubation with micromolar

Pharmacology and putative functions of murine fpr receptors

It is important to keep in mind that the extrapolation of data between murine and human species is not obvious in the case of formyl peptide receptors. Indeed, the FPR gene cluster has undergone differential expansion after divergence of human and mouse species (Fig. 1). In addition, the larger number of receptors encoded by the mouse genome does not appear to correspond to a multiplication of subtypes. Indeed, most of the mouse receptors do not respond to the main high affinity ligands

Structure-function relationships of formyl peptide receptors

The ligand-binding domains of FPR and FPRL1 have been analysed by the classical approaches of receptor chimaeras and site-directed mutagenesis. Chimaeras between C5aR and FPR showed that virtually all domains of FPR are involved in the high affinity binding of fMLF [139]. A comparison of the sequences of human FPR and FPRL1, and their rabbit and mouse counterparts, together with the construction of FPR-FPRL1 chimeras and point mutants, confirmed the involvement of multiple non-contiguous

Conclusions and perspectives

Formyl peptide receptors play clearly an important role in the regulation of immune functions. They display complex functional properties, partly due to their high promiscuity, but also to the fact that activation of the receptors can promote either stimulation or inhibition of the immune response, depending on the ligand, its concentration, and the cell type involved. These receptors have the unique peculiarity among G protein-coupled receptors to be activated by a very diverse set of natural

Acknowledgements

The work performed in the laboratory of the authors was supported by the Belgian programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming, the Life Sci Health 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

Dr Isabelle Migeotte received her MD from the Free University of Brussels in 1998 and her PhD in 2005. She is presently post-doctoral fellow at the Memorial Sloan-Kettering Cancer Center in New York City. Her PhD was dedicated to the characterization of new ligands of the FPRL2 receptor.

References (150)

  • M. Czapiga et al.

    Human platelets exhibit chemotaxis using functional N-formyl peptide receptors

    Exp Hematol

    (2005)
  • M. Harada et al.

    N-formylated humanin activates both formyl peptide receptor-Like 1 and 2

    Biochem Biophys Res Commun

    (2004)
  • R. Selvatici et al.

    Signal transduction pathways triggered by selective formylpeptide analogues in human neutrophils

    Eur J Pharmacol

    (2006)
  • T. Christophe et al.

    The synthetic peptide Trp-Lys-Tyr-Met-Val-Met-NH2 specifically activates neutrophils through FPRL1/lipoxin A(4) receptors and is an agonist for the orphan monocyte-expressed chemoattractant receptor FPRL2

    J Biol Chem

    (2001)
  • K. Wenzel-Seifert et al.

    Quantitative analysis of formyl peptide receptor coupling to G(i)alpha(1) G(i)alpha(2), and G(i)alpha(3)

    J Biol Chem

    (1999)
  • K. Wenzel-Seifert et al.

    High constitutive activity of the human formyl peptide receptor

    J Biol Chem

    (1998)
  • S.H. Baek et al.

    Identification of the peptides that stimulate the phosphoinositide hydrolysis in lymphocyte cell lines from peptide libraries

    J Biol Chem

    (1996)
  • J. Karlsson et al.

    The peptide Trp-Lys-Tyr-Met-Val-D-Met activates neutrophils through the formyl peptide receptor only when signaling through the formylpeptde receptor Like 1 is blocked—a receptor switch with implications for signal transduction studies with inhibitors and receptor antagonists

    Biochem Pharmacol

    (2006)
  • S.B. Su et al.

    T20/DP178, an ectodomain peptide of human immunodeficiency virus type 1 gp41, is an activator of human phagocyte N-formyl peptide receptor

    Blood

    (1999)
  • M.C. Braun et al.

    Activation of the formyl peptide receptor by the HIV-derived peptide T-20 suppresses interleukin-12 p70 production by human monocytes

    Blood

    (2001)
  • A. Walther et al.

    A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR

    Mol Cell

    (2000)
  • A. Rosengarth et al.

    A Calcium-driven Conformational switch of the N-terminal and Core domains of annexin A1

    J Mol Biol

    (2003)
  • S. Arur et al.

    Annexin I Is an endogenous ligand that mediates apoptotic cell engulfment

    Dev Cell

    (2003)
  • R.P.G. Hayhoe et al.

    Annexin 1 and its bioactive peptide inhibit neutrophil-endothelium interactions under flow: indication of distinct receptor involvement

    Blood

    (2006)
  • M. Perretti

    The annexin 1 receptor(s): is the plot unravelling?

    Trends in Pharmacol Sci

    (2003)
  • M. Perretti et al.

    Involvement of the Receptor for formylated peptides in the in vivo anti-migratory actions of annexin 1 and its mimetics

    Am J Pathol

    (2001)
  • F.N.E. Gavins et al.

    Leukocyte antiadhesive actions of annexin 1: ALYR- and FPR-related anti-inflammatory mechanisms

    Blood

    (2003)
  • Y. Yamamoto et al.

    Inhibitory effects of spinorphin, a novel endogenous regulator, on chemotaxis, O-2 generation, and exocytosis by N-formylmethionyl-leucyl-phenylalanine (FMLP)-stimulated neutrophils

    Biochem Pharmacol

    (1997)
  • H.Y. Lee et al.

    Lysophosphatidic acid is a mediator of Trp-Lys-Tyr-Met-Val-D-Met-induced calcium influx

    Biochem Biophys Res Commun

    (2004)
  • E.J. Jo et al.

    Activation of formyl peptide receptor-Like 1 by WKYMVm induces serine phosphorylation of STAT3, which inhibits its tyrosine phosphorylation and nuclear translocation induced by hydrogen peroxide

    Life Sci

    (2004)
  • Y.S. Bae et al.

    Novel chemoattractant peptides for human leukocytes

    Biochem Pharmacol

    (2003)
  • Y.S. Bae et al.

    Identification of novel chemoattractant peptides for human leukocytes

    Blood

    (2001)
  • X. Deng et al.

    A Synthetic peptide derived from human immunodeficiency virus type 1 gp120 downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G protein-coupled receptor FPRL1/LXA4R

    Blood

    (1999)
  • Y.Y. Le et al.

    N36, a synthetic N-terminal heptad repeat domain of the HIV-1 envelope protein gp41, is an activator of human phagocytes

    Clin Immunol

    (2000)
  • S.M. Shawar et al.

    Peptides from the amino-terminus of mouse mitochondrially encoded nadh dehydrogenase subunit 1 are potent chemoattractants

    Biochem Biophys Res Commun

    (1995)
  • C.R. Wang et al.

    Nonclassical binding of formylated peptide in crystal-structure of the Mhc Class-Ib molecule H2-M3

    Cell

    (1995)
  • J.F. Maddox et al.

    Lipoxin A4 stable analogs are potent mimetics that stimulate human monocytes and THP-1 cells via a G protein-linked lipoxin A4 receptor

    J Biol Chem

    (1997)
  • H.D. Perez et al.

    Cloning of the gene coding for a human receptor for formyl peptides—characterization of a promoter region and evidence for polymorphic expression

    Biochemistry

    (1992)
  • V. Alvarez et al.

    A Physical map of two clusters containing the genes for 6 proinflammatory receptors

    Immunogenetics

    (1994)
  • M.R. Gwinn et al.

    Single nucleotide polymorphisms of the N-formyl peptide receptor in localized juvenile periodontitis

    J Periodontol

    (1999)
  • A. Sahagun-Ruiz et al.

    Contrasting evolution of the human leukocyte N-formylpeptide receptor subtypes FPR and FPRL1R

    Genes Immun

    (2001)
  • V. Alvarez et al.

    Molecular evolution of the N-formyl peptide and C5a receptors in non-human primates

    Immunogenetics

    (1996)
  • T. Takano et al.

    Aspirin-triggered 15-Epi-Lipoxin A4 (LXA4) and LXA4 stable analogues are potent inhibitors of acute inflammation: evidence for anti-inflammatory receptors

    J Exp Med

    (1997)
  • J.K. Hartt et al.

    N-formylpeptides induce two distinct concentration optima for mouse neutrophil chemotaxis by differential interaction with two N-formylpeptide receptor (FPR) subtypes: molecular characterization of FPR2, a second mouse neutrophil FPR

    J Exp Med

    (1999)
  • R.D. Ye et al.

    The rabbit neutrophil N-formyl peptide receptor—cDNA cloning, expression, and structure-function implications

    J Immunol

    (1993)
  • N. Chiang et al.

    A novel rat lipoxin A(4) receptor that is conserved in structure and function

    Br J Pharmacol

    (2003)
  • E.L. Becker et al.

    Broad immunocytochemical localization of the formylpeptide receptor in human organs, tissues, and cells

    Cell Tissue Res

    (1998)
  • S.E. VanCompernolle et al.

    Expression and function of formyl peptide receptors on human fibroblast cells

    J Immunol

    (2003)
  • D. Yang et al.

    Human dendritic cells express functional formyl peptide receptor-Like-2 (FPRL2) throughout maturation

    J Leukoc Biol

    (2002)
  • D. Yang et al.

    Differential regulation of formyl peptide receptor-Like 1 expression during the differentiation of monocytes to dendritic cells and macrophages

    J Immunol

    (2001)
  • Cited by (0)

    Dr Isabelle Migeotte received her MD from the Free University of Brussels in 1998 and her PhD in 2005. She is presently post-doctoral fellow at the Memorial Sloan-Kettering Cancer Center in New York City. Her PhD was dedicated to the characterization of new ligands of the FPRL2 receptor.

    Dr. Marc Parmentier is vice-director of the Institute of Interdisciplinary Research of the Free University of Brussels (ULB) Medical School. He obtained his MD from ULB in 1981, and his PhD in 1990. His group is dedicated to the characterization of new G protein-coupled receptors, particularly in the frame of the control of immune responses.

    View full text