The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

Abstract

The formyl peptide receptors (FPRs) are G protein-coupled receptors that transduce chemotactic signals in phagocytes and mediate host-defense as well as inflammatory responses including cell adhesion, directed migration, granule release and superoxide production. In recent years, the cellular distribution and biological functions of FPRs have expanded to include additional roles in homeostasis of organ functions and modulation of inflammation. In a prototype, FPRs recognize peptides containing N-formylated methionine such as those produced in bacteria and mitochondria, thereby serving as pattern recognition receptors. The repertoire of FPR ligands, however, has expanded rapidly to include not only N-formyl peptides from microbes but also non-formyl peptides of microbial and host origins, synthetic small molecules and an eicosanoid. How these chemically diverse ligands are recognized by the three human FPRs (FPR1, FPR2 and FPR3) and their murine equivalents is largely unclear. In the absence of crystal structures for the FPRs, site-directed mutagenesis, computer-aided ligand docking and structural simulation have led to the identification of amino acids within FPR1 and FPR2 that interact with several formyl peptides. This review article summarizes the progress made in the understanding of FPR ligand diversity as well as ligand recognition mechanisms used by these receptors.

4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists

“…Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCR) that play an important role in leukocyte activation and chemotaxis [1]. In humans, there are three FPR isoforms: FPR1, FPR2, and FPR3 [1].…”

“…In humans, there are three FPR isoforms: FPR1, FPR2, and FPR3 [1]. FPR1 is expressed on a variety of cell types, including neutrophils, macrophages, natural killer (NK) cells, immature dendritic cells, astrocytes, microglial cells, hepatocytes, and bone marrow-derived mesenchymal stem cells [1–6].…”

“…In humans, there are three FPR isoforms: FPR1, FPR2, and FPR3 [1]. FPR1 is expressed on a variety of cell types, including neutrophils, macrophages, natural killer (NK) cells, immature dendritic cells, astrocytes, microglial cells, hepatocytes, and bone marrow-derived mesenchymal stem cells [1–6]. FPR1 was originally identified as a receptor for N -formyl peptides, which are produced by bacteria but can also be released from damaged mitochondria during tissue injury [2, 7, 8].…”

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

“…Later studies have revealed that mitochondrial NFPs are recognized by high-affinity formyl peptides receptors (FPRs) (Dahlgren et al, 2016). FPRs constitute a small group of 7-transmembrane domain, G-protein-coupled receptors that are expressed not only on neutrophils, monocytes and dendritic cells but also on hepatocytes, endothelial cells and cells of the nervous system (He and Ye, 2017). Indeed, a recent study has suggested a pathogenic role of mitochondrial NFPs in human disease (Dorward et al, 2017).…”

Annexins in Translational Research: HIDDEN Treasures to Be Found

“…neutrophils, macrophages, dendritic cells) but also found in endo-and epithelial cells [62]. A broad range of FPR1 ligands, both agonist and antagonists, have been described [63], and autocrine/paracrine signalling of externalized AnxA1 protein and/or its peptides via the FPRs might explain its wellknown immune-modulatory and pro-resolving actions. Upregulation of AnxA1 expression is observed in several inflammatory conditions [64] and thought to function in resolution and tissue protection [65].…”