Review
Receptors for chemotactic formyl peptides as pharmacological targets

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Abstract

Leukocytes accumulate at sites of inflammation and immunological reaction in response to locally existing chemotactic mediators. N-formyl peptides, such as fMet-Leu-Phe (fMLF), are some of the first identified and most potent chemoattractants for phagocytic leukocytes. In addition to the bacterial peptide fMLF and the putative endogenously produced formylated peptides, a number of novel peptide agonists have recently been identified that selectively activate the high-affinity fMLF receptor FPR and/or its low-affinity variant FPRL1, both of which belong to the seven-transmembrane (STM), G protein-coupled receptor (GPCR) superfamily. These agonists include peptide domains derived from the envelope proteins of human immunodeficiency virus type 1 (HIV-1) and at least three amyloidogenic polypeptides, the human acute phase protein serum amyloid A, the 42 amino acid form of β amyloid peptide and a 21 amino acid fragment of human prion. Furthermore, a cleavage fragment of neutrophil granule-derived bactericidal cathelicidin, LL-37, is also a chemotactic agonist for FPRL1. Activation of formyl peptide receptors results in increased cell migration, phagocytosis, release of proinflammatory mediators, and the signaling cascade culminates in heterologous desensitization of other STM receptors including chemokine receptors CCR5 and CXCR4, two coreceptors for HIV-1. Thus, by interacting with a variety of exogenous and host-derived agonists, formyl peptide receptors may play important roles in proinflammatory and immunological diseases and constitute a novel group of pharmacological targets.

Introduction

N-formyl peptides are cleavage products of bacterial and mitochondrial proteins, and serve as potent chemoattractants for mammalian phagocytic leukocytes [1], [2], [3], [4]. The synthetic analogue of the bacterial formyl-methionyl-leucyl-phenylalanine (fMLF) activates at least two seven-transmembrane (STM), G protein-coupled receptors (GPCRs), the high-affinity FPR and its low-affinity variant FPRL1, in human cells. After binding to the receptors, fMLF activates phagocytic leukocytes through a typical pertussis toxin (PTX) sensitive, G protein-mediated signaling cascade, which leads to increases in cell migration, phagocytosis, and release of proinflammatory mediators [5], [6]. Activation of FPR and FPRL1 by agonists subsequently interferes with cellular responses to a number of chemoattractants that use other unrelated STM receptors via heterologous receptor desensitization [7], [8], [9], [10].

Although the receptors for chemotactic formyl peptides were identified and cloned a number of years ago, their biological significance remained poorly understood until recently. Targeted disruption of the gene coding for the mouse counterpart of FPR rendered mice more susceptible to bacterial infection without significant phenotypic alteration [11], suggesting that FPR may be involved in the innate host defense based on recognition of bacterium-derived agonists. During the past few years, a wide variety of novel agonists that activate either or both FPR and FPRL1 have been identified. These agonists include peptide domains derived from human immunodeficiency virus type 1 (HIV-1) envelope proteins, small synthetic peptides selected from random peptide libraries, and host-derived peptide or lipid chemoattractants. Interestingly, most of these chemoattractants specifically interact with the low-affinity fMLF receptor FPRL1, and among a number of FPRL1-specific chemotactic agonists identified so far, at least three of them, the serum amyloid A (SAA), the 42 amino acid form of amyloid β (Aβ42) and a peptide fragment of the human prion protein (PrP106–126), are amyloidogenic polypeptides [12], [13], [14]. Thus, FPRL1 may play a significant role in proinflammatory responses seen in systemic amyloidosis, Alzheimer's disease (AD), and prion diseases, in which infiltration of activated mononuclear phagocytes at the sites of lesions is a common feature. The purpose of this review is to briefly outline some recent progress in the research of formyl peptide receptors and to identify these receptors as potential targets for immunopharmacologic intervention.

Section snippets

An overview of N-formyl peptide receptors

In human, there are three genes encoding two functional N-formylpeptide receptors, FPR and FPRL1 (FPR-like 1), and a putative receptor FPRL2 (FPR-like 2) [15], [16], [17], [18]. All three genes cluster on chromosome 19q13.3. FPR and FPRL1 are STM, G protein-coupled receptors and share 69% identity at the amino acid level [5], [6]. FPR binds fMLF with high affinity with Kd values in the picomolar to low nanomolar range and is activated by fMLF at correspondingly low concentrations to mediate

Novel agonists for FPR and FPRL1

In addition to bacterial fMLF, a number of protein and peptide agonists that preferentially activate either or both FPR and FPRL1 have been identified (Table 1). WKYMVm, a hexapeptide representing a modified sequence isolated from a random peptide library, was initially reported to be a very potent stimulant of human B lymphocytes, monocytic cell lines, as well as peripheral blood neutrophils [53], [54]. It was subsequently found that this peptide uses both FPR and FPRL1, with a markedly higher

Antagonists for formyl peptide receptors

The potential involvement of fMLF receptors in microbial infection and host inflammatory responses prompted studies in search of antagonists, which are important for delineating signal transduction cascade associated with receptor activation, and as a basis for developing therapeutic agents. Several antagonists have been reported for the high-affinity fMLF receptor FPR (Table 1 and Fig. 2). Replacement of the N-formyl group of fMLF with a t-butyloxycarbonyl (tBOC) or isopropylureido group

HIV-infection

Formyl peptide receptors have not been reported to act as HIV-1 coreceptors despite the fact that HIV-1 envelope proteins contain multiple domains that are activators of either or both FPR and FPRL1 [9], [58], [59], [60], [61], [62]. There has been no experimental evidence to show a direct interaction between intact HIV-1 envelope proteins and the formyl peptide receptors. Recombinant gp120 and gp41 of HIV-1 have been reported to downregulate the expression and function of the receptors for

Concluding remarks

During the past few years, substantial progress has been made in the understanding of the biological roles of once elusive formyl peptide receptors. The original hypothesis that the formyl peptide receptors may be involved in host anti-microbial defense was supported by observations that FPR gene knockout mice were more susceptible to bacterial infection [11]. However, the identification of novel and host-derived agonists for both FPR and FPRL1 broadens the spectrum of functional significance

Acknowledgements

The authors thank Dr. Joost J. Oppenheim for reviewing the manuscript; Drs. Philip M. Murphy and Ji-Liang Gao for their collaboration, and Nancy M. Dunlop for her technical support. The secretarial assistance by C. Fogle and C. Nolan is gratefully acknowledged. Y. Yang is a visiting scientist from Western China University of Medical Sciences, PR China, and is supported by funds provided by the Ministry of Education, PR China, and the Office of International Affairs, NCI, NIH, USA.

References (112)

  • M. Durstin et al.

    Differential expression of members of the N-formylpeptide receptor gene cluster in human phagocytes

    Biochem. Biophys. Res. Commun.

    (1994)
  • M. Lacy et al.

    Expression of the receptors for the C5a anaphylatoxin, interleukin-8 and FMLP by human astrocytes and microglia

    J. Neuroimmunol.

    (1995)
  • M. Keitoku et al.

    FMLP actions and its binding sites in isolated human coronary arteries

    J. Mol. Cell Cardiol.

    (1997)
  • J.L. Gao et al.

    Species and subtype variants of the N-formyl peptide chemotactic receptor reveal multiple important functional domains

    J. Biol. Chem.

    (1993)
  • K.M. Thomas et al.

    Molecular cloning of the fMet-Leu-Phe receptor from neutrophils

    J. Biol. Chem.

    (1990)
  • Y. Le et al.

    Expression of functional formyl peptide receptors by human astrocytoma cell lines

    J. Neuroimmunol.

    (2000)
  • H. Ali et al.

    Differences in phosphorylation of formylpeptide and C5a chemoattractant receptors correlated with differences in desensitization

    J. Biol. Chem.

    (1993)
  • B. Haribabu et al.

    Chemoattractant receptors activate distinct pathways for chemotaxis and secretion: role of G-protein usage

    J. Biol. Chem.

    (1999)
  • P. Gierschik et al.

    Two distinct Gi-proteins mediate formyl peptide receptor signal transduction in human leukemia (HL-60) cells

    J. Biol. Chem.

    (1989)
  • J.F. Klinker et al.

    Differential activation of dibutyryl cAMP-differentiated HL-60 human leukemia cells by chemoattractants

    Biochem. Pharmacol.

    (1994)
  • K. Wenzel-Seifert et al.

    Quantitative analysis of formyl peptide receptor coupling to Giα1, Giα2, and Giα3

    J. Biol. Chem.

    (1999)
  • D. Leopoldt et al.

    Gbetagamma stimulates phosphoinositide 3-kinase-gamma by direct interaction with two domains of the catalytic p110 subunit

    J. Biol. Chem.

    (1998)
  • A. Ptasznik et al.

    G protein-coupled chemoattractant receptors regulate lyn tyrosine kinase-Shc adapter protein signaling complexes

    J. Biol. Chem.

    (1995)
  • E.R. Prossnitz

    Desensitization of N-formylpeptide receptor-mediated activation is dependent upon receptor phosphorylation

    J. Biol. Chem.

    (1997)
  • M.H. Hsu et al.

    Phosphorylation of the N-formyl peptide receptor is required for receptor internalization but not chemotaxis

    J. Biol. Chem.

    (1997)
  • T.A. Bennett et al.

    Arrestin binding to the G protein-coupled N-formyl peptide receptor is regulated by the conserved “DRY” sequence

    J. Biol. Chem.

    (2000)
  • K. Wenzel-Seifert et al.

    High constitutive activity of the human formyl peptide receptor

    J. Biol. Chem.

    (1998)
  • 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)
  • J.K. Hartt et al.

    The HIV-1 cell entry inhibitor T-20 potently chemoattracts neutrophils by specifically activating the N-formylpeptide receptor

    Biochem. Biophys. Res. Commun.

    (2000)
  • 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)
  • X. Deng et al.

    A synthetic peptide derived from HIV-1 gp120 down-regulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the seven-transmembrane G protein-coupled receptor FPRL1/LXA4R

    Blood

    (1999)
  • 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. de Paulis et al.

    Cyclosporin H is a potent and selective competitive antagonist of human basophil activation by N-formyl-methionyl-leucyl-phenylalanine

    J. Allergy Clin. Immunol.

    (1996)
  • H. Ali et al.

    Chemoattractant receptor cross-desensitization

    J. Biol. Chem.

    (1999)
  • M.J. Stone

    Amyloidosis: a final common pathway for protein deposition in tissues

    Blood

    (1990)
  • C. Bonaiuto et al.

    Activation of nuclear factor-kappa B by beta-amyloid peptides and interferon-gamma in murine microglia

    J. Neuroimmunol.

    (1997)
  • K.A. Dzenko et al.

    Suppression of A beta-induced monocyte neurotoxicity by antiinflammatory compounds

    J. Neuroimmunol.

    (1997)
  • E. Schiffmann et al.

    N-formylmethionyl peptides as chemoattractants for leukocytes

    Proc. Natl. Acad. Sci. U. S. A.

    (1975)
  • E. Schiffmann et al.

    The isolation and partial characterization of neutrophil chemotactic factors from Escherichia coli

    J. Immunol.

    (1975)
  • H. Carp

    Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils

    J. Exp. Med.

    (1982)
  • P.M. Murphy

    The N-formyl peptide chemotactic receptors

  • J.L. Gao et al.

    Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor

    J. Exp. Med.

    (1999)
  • S.B. Su et al.

    A seven-transmembrane, G-protein-coupled receptor, FPRL1, mediates the chemotactic activity of serum amyloid A for human phagocytic cells

    J. Exp. Med.

    (1999)
  • Y. Le et al.

    Amyloid β42 activates a G protein-coupled chemoattractant receptor FPR-like 1

    J. Neurosci.

    (2000)
  • Y. Le et al.

    The neurotoxic prion peptide fragment PrP(106–126) is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like 1

    J. Immunol.

    (2001)
  • H. Nomura et al.

    Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors

    Int. Immunol.

    (1993)
  • R. McCoy et al.

    N-formylpeptide and complement C5a receptors are expressed in liver cells and mediate hepatic acute phase gene regulation

    J. Exp. Med.

    (1995)
  • S. Sozzani et al.

    Migration of dendritic cells in response to formyl peptides, C5a, and a distinct set of chemokines

    J. Immunol.

    (1995)
  • E.L. Becker et al.

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

    Cell Tissue Res.

    (1998)
  • V. Alvarez et al.

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

    Immunogenetics

    (1996)
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