The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase

Abstract

Neutrophils expressing formyl peptide receptor 2 (FPR2) play key roles in host defense, immune regulation, and resolution of inflammation. Consequently, the search for FPR2-specific modulators has attracted much attention due to its therapeutic potential. Earlier described agonists for this receptor display potent activity for the human receptor (FPR2) but low activity for the mouse receptor orthologue (Fpr2), rendering them inapplicable in murine models of human disease. Here we describe a novel FPR2 agonist, the proteolytically stable ␣-peptide/␤-pep- The molecular basis for directional neutrophil migration toward inflammatory sites is their ability to sense "danger signals" produced by microorganisms (i.e. pathogen-associated molecular patterns) and damaged host cells or tissues (i.e. damage-associated molecular patterns) (1). Human neutrophils express two members of the formyl peptide receptor family (FPR1 3 and FPR2), belonging to the family of G-protein-coupled receptors (GPCRs), which recognize pathogen-associated molecular patterns in the form of peptides with an N-terminal formyl-methionine residue, originating from bacterial (and mitochondrial) protein synthesis (2, 3). In addition, human neutrophils express GPCRs that recognize endogenous chemoattractants and damage-associated molecular patterns, including the split product of complement component C5 (C5a, recognized by C5aR), leukotriene LTB 4 (recognized by BLT1), the chemokine IL-8 (CXCL8, recognized by CXCR1 and CXCR2), platelet-activating factor (PAF, recognized by PAFR), and the nucleotide ATP (recognized by P2Y 2 R) (4, 5). Although the two human neutrophil FPRs, FPR1 and FPR2, display significant sequence similarity, they have distinct, albeit partially overlapping, ligand recognition profiles (2, 6, 7).The mouse genome contains at least eight mouse Fprs, among which Fpr1 and Fpr2 are regarded as the orthologues of the receptors expressed in human neutrophils (8, 9). Studies using mice deficient in Fpr1 or Fpr2 have demonstrated roles of these receptors not only in host defense but also in immune regulation and in the resolution of inflammation (10 -12). The therapeutic potential of targeting these receptors in inflammatory/infectious conditions, such as atherosclerosis, cancer, neurodegenerative diseases, and sepsis (see a recent review (13)), justifies the search for receptor-specific ligands that can function as agonists, antagonists, or allosteric modulators. However, a direct translation of knowledge between humans and

Hemin impairs resolution of inflammation via microRNA‐144‐3p‐dependent downregulation of ALX/FPR2

“…This receptor is expressed in a variety of cell types, such as endothelial cells, neutrophils, and macrophages . Much is known about the proinflammatory functions of neutrophils; however, a more recent work suggests that neutrophils expressing ALX/FPR2 play a key role in host defense and resolution of inflammation . Here, we hypothesize that hemin can regulate ALX/FPR2 expression, resulting in impairment of neutrophils pro‐resolution responses triggered by ALX/FPR2 agonist.…”

“…Lipoxin A 4 receptor (ALX)/formyl peptide receptor 2 (FPR2) acted as a pivotal checkpoint in host defense, inhibited the recruitment of PMNs into the inflamed site, and promoted PMN apoptosis by recognizing pro‐resolving mediators, such as lipoxin A 4 , resolvin D1 (RvD1), and annexin A1 . A more recent work suggests that neutrophils expressing ALX/FPR2 play a key role in the resolution of inflammation and immune regulation . Dufton et al found that the inhibition of PMN recruitment by annexin A1 was attenuated largely in Fpr2 −/− (the murine homologue of ALX/FPR2) mice, leading to greater acute inflammation and a prolongation of inflammatory arthritis.…”

Formylated MHC Class Ib Binding Peptides Activate Both Human and Mouse Neutrophils Primarily through Formyl Peptide Receptor 1

“…Out of the eight murine members of the Fpr gene family, the Fpr1 and Fpr2 are most similar to the human receptors both when it comes to sequence similarities, expression patterns, and functional properties [7]. It should be noticed that until recently no formylated peptide had been shown to activate FPR2/Fpr2, but it is now clear that PSMα peptides are specifically recognized by these receptors [12, 14, 24, 32]. We know now that FPR2 displays also binding affinity for formyl peptides, but the peptide size matters, i.e., large formyl peptides prefer FPR2 whereas short formyl peptides have high affinity for FPR1 [12, 13, 33].…”

Formyl peptide derived lipopeptides disclose differences between the receptors in mouse and men and call the pepducin concept in question

“…We also recently showed that some of the most potent and selective antagonists for the human FPRs lack effects on their mouse counterparts, cyclosporin H and PBP 10 being prominent examples [ 12 ]. We have also identified lipidated peptidomimetics and a set of formylated MHC class Ib binding peptides as novel agonists for both human and mouse receptors, but there were no direct correlations between the activities induced by these agonists in human and mouse neutrophils [ 13 , 14 ]. This clearly implies that when comparing mice and men there are some similarities between the receptor orthologous in the two species, but there are also important differences in the ligand recognition profiles.…”