ReviewReceptors for chemotactic formyl peptides as 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.
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