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The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation

  • David A. Dorward
    Correspondence
    Address correspondence to David A. Dorward, Ph.D., MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom.
    Affiliations
    Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom
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  • Christopher D. Lucas
    Affiliations
    Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom
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  • Gavin B. Chapman
    Affiliations
    Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom
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  • Christopher Haslett
    Affiliations
    Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom
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  • Kevin Dhaliwal
    Affiliations
    Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom
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  • Adriano G. Rossi
    Affiliations
    Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, Edinburgh, United Kingdom
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Open AccessPublished:March 16, 2015DOI:https://doi.org/10.1016/j.ajpath.2015.01.020
      Neutrophil migration to sites of inflammation and the subsequent execution of multiple functions are designed to contain and kill invading pathogens. These highly regulated and orchestrated processes are controlled by interactions between numerous receptors and their cognate ligands. Unraveling and identifying those that are central to inflammatory processes may represent novel therapeutic targets for the treatment of neutrophil-dominant inflammatory disorders in which dysregulated neutrophil recruitment, function, and elimination serve to potentiate rather than resolve an initial inflammatory insult. The first G protein–coupled receptor to be described on human neutrophils, formyl peptide receptor 1 (FPR1), is one such receptor that plays a significant role in the execution of these functions through multiple intracellular signaling pathways. Recent work has highlighted important observations with regard to both receptor function and the importance and functional relevance of FPR1 in the pathogenesis of a range of both sterile and infective inflammatory conditions. In this review, we explore the multiple components of neutrophil migration and function in both health and disease, with a focus on the role of FPR1 in these processes. The current understanding of FPR1 structure, function, and signaling is examined, alongside discussion of the potential importance of FPR1 in inflammatory diseases suggesting that FPR1 is a key regulator of the inflammatory environment.
      More than 100 years ago, Metchnikoff described microphagocytes as important responders to sterile injury in starfish larvae.
      • Cavaillon J.M.
      The historical milestones in the understanding of leukocyte biology initiated by Elie Metchnikoff.
      Now known to be neutrophils, they are key effector cells of the innate immune system and are pivotal in the containment and clearance of initial noxious stimuli of either infective or sterile origin.
      • Jaillon S.
      • Galdiero M.R.
      • Del Prete D.
      • Cassatella M.A.
      • Garlanda C.
      • Mantovani A.
      Neutrophils in innate and adaptive immunity.
      Accounting for 50% to 70% of circulating human leukocytes, these polymorphonuclear granulocytes patrol the vasculature and rapidly migrate into tissues in response to chemotactic signals.
      • Nourshargh S.
      • Hordijk P.L.
      • Sixt M.
      Breaching multiple barriers: leukocyte motility through venular walls and the interstitium.
      On arrival, neutrophils execute a variety of antimicrobial functions, including the generation of reactive oxygen species (ROS), phagocytosis of pathogens and dead and dying tissue, degranulation with the release of a variety of toxic products, expulsion of neutrophil extracellular traps, and paracrine signaling to recruit other cell types.
      • Kolaczkowska E.
      • Kubes P.
      Neutrophil recruitment and function in health and inflammation.
      Disruption of these processes or overwhelming neutrophil recruitment can cause significant dysregulation of the inflammatory cascade, resulting in failed resolution of inflammation, tissue injury, and acute or chronic disease.
      The predominant mechanisms through which neutrophils sense inflammatory stimuli and surrounding environments are a plethora of cell surface receptors principally within the G protein–coupled receptor (GPCR) family. The first GPCR to be described on the human neutrophil was formyl peptide receptor 1 (FPR1) which, when activated, triggers a wide variety of functions, including chemotaxis, degranulation, ROS production, and phagocytosis.
      • Boulay F.
      • Tardif M.
      • Brouchon L.
      • Vignais P.
      Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA.
      • Ye R.D.
      • Boulay F.
      • Wang J.M.
      • Dahlgren C.
      • Gerard C.
      • Parmentier M.
      • Serhan C.N.
      • Murphy P.M.
      International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
      Although descriptions of FPR1 functions in vitro are well documented, increasing attention is being paid to its in vivo role, influence, and importance in the pathogenesis of both infective and sterile acute inflammatory disease.
      The principal ligands for FPR1 are bacterial and mitochondrial formylated peptides, actively secreted by invading pathogens or passively released from dead and dying host cells after tissue injury. During infection, pathogens target and destroy host tissue with the simultaneous release of both bacteria-derived (when the pathogen is of bacterial origin) and host-derived formylated peptides (from host mitochondria), thereby linking FPR1 in both infective and sterile inflammatory processes. This review therefore provides an overview of the structure, signaling, and pathological functions of FPR1 as well as a focus on the recent developments in the understanding of formylated peptides and neutrophil FPR1 in the context of infective and sterile inflammation.

      Formyl Peptide Receptors

      The binding of the N-formyl methionine motifs of bacterial- and mitochondrial-derived peptides to FPR1 was initially described over 3 decades ago and was the starting point for the subsequent dissection of the many G-protein signaling cascades within neutrophils.
      • Carp H.
      Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils.
      • Schiffmann E.
      • Corcoran B.A.
      • Wahl S.M.
      N-formylmethionyl peptides as chemoattractants for leucocytes.
      The human FPR family constitutes FPR1, FPR2/ALX (lipoxin receptor), and FPR3, which are well-conserved GPCRs that have pluripotent and diverse roles in the initiation, propagation, and resolution of inflammation.
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
      FPR1 was the first neutrophil GPCR to be cloned and sequenced, identifying it as a 350-residue protein with seven hydrophobic segments (Figure 1).
      • Boulay F.
      • Tardif M.
      • Brouchon L.
      • Vignais P.
      Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA.
      A subsequent study characterized FPR1 as a seven-transmembrane receptor with the N-terminus and three loops exposed on the cell surface for ligand interactions and the C-terminus and the remaining loops found within the cytoplasm necessary for intracellular signaling.
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      Using low-stringency hybridization with FPR cDNA as the probe, two separate but relatively conserved low-affinity receptors, initially termed FPR-like 1 (FPRL1) and FPR-like 2 (FPR2L), were cloned from an mRNA library of neutrophil-like promyelocytic HL-60 cells. These receptors have since been renamed FPR2/ALX and FPR3, respectively, as more has become known about their distinct biochemical and physiological roles.
      • Ye R.D.
      • Boulay F.
      • Wang J.M.
      • Dahlgren C.
      • Gerard C.
      • Parmentier M.
      • Serhan C.N.
      • Murphy P.M.
      International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
      All three receptors are clustered together on chromosome 19q13.3 and share significant sequence homology. FPR1 has 69% amino acid identity with FPR2 and 56% with FPR3, whereas FPR2 and FPR3 share 83% identity.
      • Bao L.
      • Gerard N.P.
      • Eddy Jr., R.L.
      • Shows T.B.
      • Gerard C.
      Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19.
      Figure thumbnail gr1
      Figure 1Structure of the FPR1 receptor and key polymorphisms within the protein. Formyl peptide receptor 1 (FPR1) as a classic G-protein–coupled receptor has seven transmembrane-spanning regions with an extracellular N-terminus, whereas the C-terminus is found within the cytoplasm. Multiple amino acid substitutions have been found within the protein: recognized constitutive isoforms (green; FPR-26, FPR-98, and FPR-G6), polymorphisms associated with disease states including juvenile and aggressive periodontitis (red), hypertension in young adults (orange), gastric cancer (pink; denotes D192K), and those that have been observed but whose functional significance remains uncertain (blue).

      Formyl Peptide Receptor 1

      Regulation of FPR1 Expression

      Constitutively expressed on the surface of quiescent neutrophils, FPR1 receptor expression is rapidly up-regulated in response to a wide number of inflammatory stimuli. In vitro, these stimuli include lipopolysaccharide (LPS), platelet-activating factor, unmethylated CpG oligodinucleotides, and tumor necrosis factor α
      • Hayashi F.
      • Means T.K.
      • Luster A.D.
      Toll-like receptors stimulate human neutrophil function.
      • Kitchen E.
      • Rossi A.G.
      • Condliffe A.M.
      • Haslett C.
      • Chilvers E.R.
      Demonstration of reversible priming of human neutrophils using platelet-activating factor.
      • Sengeløv H.
      • Boulay F.
      • Kjeldsen L.
      • Borregaard N.
      Subcellular localization and translocation of the receptor for N-formylmethionyl-leucyl-phenylalanine in human neutrophils.
      • O’Flaherty J.T.
      • Rossi A.G.
      • Redman J.F.
      • Jacobson D.P.
      Tumor necrosis factor-alpha regulates expression of receptors for formyl-methionyl-leucyl-phenylalanine, leukotriene B4, and platelet-activating factor. Dissociation from priming in human polymorphonuclear neutrophils.
      ; FPR1 receptor up-regulation has also been described in the circulating neutrophils of patients with emphysema, Crohn disease, and sepsis.
      • Anton P.A.
      • Targan S.R.
      • Shanahan F.
      Increased neutrophil receptors for and response to the proinflammatory bacterial peptide formyl-methionyl-leucyl-phenylalanine in Crohn’s disease.
      • Stockley R.A.
      • Grant R.A.
      • Llewellyn-Jones C.G.
      • Hill S.L.
      • Burnett D.
      Neutrophil formyl-peptide receptors. Relationship to peptide-induced responses and emphysema.
      • Tennenberg S.D.
      • Solomkin J.S.
      Neutrophil activation in sepsis: The relationship between fmet-leu-phe receptor mobilization and oxidative activity.
      Such a rapid increase in FPR1 expression indicates its preformed presence within the cell. Subcellular fractionation and the study of neutrophil transcription within the bone marrow have determined that FPR1 synthesis occurs late in neutrophil maturation, with the receptor subsequently stored in azurophilic granules (also known as primary granules) and secretory vesicles.
      • Sengeløv H.
      • Boulay F.
      • Kjeldsen L.
      • Borregaard N.
      Subcellular localization and translocation of the receptor for N-formylmethionyl-leucyl-phenylalanine in human neutrophils.
      • Cowland J.B.
      • Borregaard N.
      The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules.
      In response to agonists such as platelet-activating factor, secretory-vesicle FPR1 alone is mobilized; however, in response to powerful stimuli such as phorbol myristate acetate, azurophilic-granule FPR1 also localizes to the cell surface.
      • Sengeløv H.
      • Boulay F.
      • Kjeldsen L.
      • Borregaard N.
      Subcellular localization and translocation of the receptor for N-formylmethionyl-leucyl-phenylalanine in human neutrophils.
      Alongside FPR1 transport from intracellular compartments, neutrophil activation increases FPR1 protein synthesis. In nonstimulated cells, FPR1 mRNA is unstable, with a t1/2 of approximately 90 minutes.
      • Mandal P.
      • Novotny M.
      • Hamilton T.A.
      Lipopolysaccharide induces formyl peptide receptor 1 gene expression in macrophages and neutrophils via transcriptional and posttranscriptional mechanisms.
      After incubation with LPS, increased FPR1 gene transcription occurs along with stabilization of the mRNA transcript (t1/2, approximately 20 hours), allowing for increased synthesis of the receptor. LPS, through myeloid differentiation marker MyD88–dependent signaling pathways, is a powerful inducer of FPR1 synthesis in mature neutrophils, whereas tumor necrosis factor α and other proinflammatory mediators also induce a similar response.
      • Hirotani T.
      • Yamamoto M.
      • Kumagai Y.
      • Uematsu S.
      • Kawase I.
      • Takeuchi O.
      • Akira S.
      Regulation of lipopolysaccharide-inducible genes by MyD88 and Toll/IL-1 domain containing adaptor inducing IFN-beta.
      • Boulay F.
      • Tardif M.
      • Brouchon L.
      • Vignais P.
      The human N-formylpeptide receptor. Characterization of two cDNA isolates and evidence for a new subfamily of G-protein-coupled receptors.
      The increases in receptor cycling and protein synthesis therefore increase FPR1 at the cell surface, facilitating the perpetuation of the inflammatory response as greater numbers of receptor are available on each cell to bind free ligand.

      Polymorphisms within FPR1

      With increasing attention being paid to the role of interindividual differences in response to infection and inflammation, variation in receptor number and function through polymorphisms within the FPR1 gene have been studied. Three isoforms of human FPR1 exist: FPR-26 (V101, N192, E346), FPR-98 (L101, N192, A346), and FPR-G6 (V101, K192, A346). These differ in amino acids 101 (the top of the third transmembrane loop), 192 (center of the second intracellular loop), and 346 (end of the C-terminus) (Figure 1).
      • Boulay F.
      • Tardif M.
      • Brouchon L.
      • Vignais P.
      The human N-formylpeptide receptor. Characterization of two cDNA isolates and evidence for a new subfamily of G-protein-coupled receptors.
      • Prossnitz E.R.
      • Ye R.D.
      The N-formyl peptide receptor: a model for the study of chemoattractant receptor structure and function.
      Functionally, FPR-98 and FPR-G6 have a partial defect in Gi-protein coupling relative to the more constitutively active FPR-26, with the amino acid glutamic acid at position 346 essential for the G-protein signaling of the latter isoform.
      • Wenzel-Seifert K.
      • Seifert R.
      Functional differences between human formyl peptide receptor isoforms 26, 98, and G6.
      Alongside these naturally occurring variants of FPR1, at least 30 other single-nucleotide polymorphisms (SNPs) have been described within the FPR1 gene.
      • Ye R.D.
      • Boulay F.
      • Wang J.M.
      • Dahlgren C.
      • Gerard C.
      • Parmentier M.
      • Serhan C.N.
      • Murphy P.M.
      International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
      Neutrophils isolated from individuals with localized juvenile periodontitis demonstrate impaired responsiveness to formyl-methyl-leucine-phenylalanine (fMLF; alias fMLP), perhaps explaining increased rates of periodontal infection through reduced migration or impaired bacterial killing capacity.
      • Gwinn M.R.
      • Sharma A.
      • De Nardin E.
      Single nucleotide polymorphisms of the N-formyl peptide receptor in localized juvenile periodontitis.
      SNPs F110S and C126W in the second intracellular loop of the receptor may well account for this phenotype. Furthermore, a T348T/T mutation, although not altering FPR1 receptor number, was associated with impaired fMLF-induced neutrophil chemotaxis and aggressive periodontitis in an African-American population.
      • Maney P.
      • Walters J.D.
      Formylpeptide receptor single nucleotide polymorphism 348T>C and its relationship to polymorphonuclear leukocyte chemotaxis in aggressive periodontitis.
      Meanwhile, the association of the C32T SNP with the development of hypertension in younger adults, as well as the D192K polymorphism with the onset of gastric carcinoma in an elderly Japanese population, have also been described, although their mechanistic and functional relevance is yet to be determined.
      • El Shamieh S.
      • Herbeth B.
      • Azimi-Nezhad M.
      • Benachour H.
      • Masson C.
      • Visvikis-Siest S.
      Human formyl peptide receptor 1 C32T SNP interacts with age and is associated with blood pressure levels.
      • Otani T.
      • Ikeda S.
      • Lwin H.
      • Arai T.
      • Muramatsu M.
      • Sawabe M.
      Polymorphisms of the formylpeptide receptor gene (FPR1) and susceptibility to stomach cancer in 1531 consecutive autopsy cases.
      In contrast, the V101L SNP is associated with increased binding affinity for the FPR1 antagonist cyclosporin H.
      • Zhou C.
      • Zhou Y.
      • Wang J.
      • Feng Y.
      • Wang H.
      • Xue J.
      • Chen Y.
      • Ye R.D.
      • Wang M.W.
      V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins.
      With increasing application of genome-wide association studies, it remains to be seen whether other SNPs are associated with altered susceptibility to inflammatory diseases or infection.

      FPR1 Ligands

      Although it was initially thought that FPR1 only bound N-formylated peptides,
      • Carp H.
      Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils.
      it is now widely recognized that the formyl group is not a prerequisite for receptor binding. The N-formylated version of any peptide containing a methionine residue at the 5′ terminus is at least 100-fold more potent than the identical nonformylated peptide. However, if the peptide contains five or more amino acids, the nonformylated moieties can also bind and activate FPR1.
      • Prossnitz E.R.
      • Ye R.D.
      The N-formyl peptide receptor: a model for the study of chemoattractant receptor structure and function.
      This finding has been further substantiated by the description of endogenous nonformylated ligands that bind FPR1, including cathepsin G, annexin A1 (AnnA1), and the recently described cytokine family with sequence similarity 19, member A4, although their functional effects differ from those of fMLF/FPR1-described functions (Table 1).
      • Wang W.
      • Li T.
      • Wang X.
      • Yuan W.
      • Cheng Y.
      • Zhang H.
      • Xu E.
      • Zhang Y.
      • Shi S.
      • Ma D.
      • Han W.
      FAM19A4 is a novel cytokine ligand of formyl peptide receptor 1 (FPR1) and is able to promote the migration and phagocytosis of macrophages.
      • Cooray S.N.
      • Gobbetti T.
      • Montero-Melendez T.
      • McArthur S.
      • Thompson D.
      • Clark A.J.
      • Flower R.J.
      • Perretti M.
      Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses.
      For example, the neutrophil granule protein cathepsin G binding to FPR1 is unable to induce intracellular calcium flux but does, however, result in mitogen-activated protein kinase (MAPK) phosphorylation and neutrophil chemotaxis and dendritic cell recruitment.
      • Sun R.
      • Iribarren P.
      • Zhang N.
      • Zhou Y.
      • Gong W.
      • Cho E.H.
      • Lockett S.
      • Chertov O.
      • Bednar F.
      • Rogers T.J.
      • Oppenheim J.J.
      • Wang J.M.
      Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor.
      It is postulated that this discrepancy in receptor function is likely attributable to low-affinity binding, thereby inducing isolated components of the inflammatory cascade.
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      Similarly, AnnA1 and its N-terminal peptide derivative Ac2-26 bind to FPR1 and induce anti-inflammatory and proresolution effects rather than a proinflammatory response through a variety of effects, including receptor heterodimerization with FPR2.
      • Leoni G.
      • Alam A.
      • Neumann P.A.
      • Lambeth J.D.
      • Cheng G.
      • McCoy J.
      • Hilgarth R.S.
      • Kundu K.
      • Murthy N.
      • Kusters D.
      • Reutelingsperger C.
      • Perretti M.
      • Parkos C.A.
      • Neish A.S.
      • Nusrat A.
      Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.
      • Cooray S.N.
      • Gobbetti T.
      • Montero-Melendez T.
      • McArthur S.
      • Thompson D.
      • Clark A.J.
      • Flower R.J.
      • Perretti M.
      Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses.
      Table 1The Principal Cell Types that Express Human Formyl Peptide Receptors and the Predominant Agonists and Antagonists of the Receptors
      Receptor/cell typeAgonistsAntagonists
      FPR1
       Neutrophils
      • Schiffmann E.
      • Corcoran B.A.
      • Wahl S.M.
      N-formylmethionyl peptides as chemoattractants for leucocytes.
      N-formylated peptides
      • Carp H.
      Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils.
      Cyclosporin H
      • Zhang Q.
      • Raoof M.
      • Chen Y.
      • Sumi Y.
      • Sursal T.
      • Junger W.
      • Brohi K.
      • Itagaki K.
      • Hauser C.J.
      Circulating mitochondrial DAMPs cause inflammatory responses to injury.
       Macrophages
      • Mandal P.
      • Novotny M.
      • Hamilton T.A.
      Lipopolysaccharide induces formyl peptide receptor 1 gene expression in macrophages and neutrophils via transcriptional and posttranscriptional mechanisms.
      Synthetic fMLF
      • Boulay F.
      • Tardif M.
      • Brouchon L.
      • Vignais P.
      Synthesis and use of a novel N-formyl peptide derivative to isolate a human N-formyl peptide receptor cDNA.
      Cyclosporin A
      • Zhou C.
      • Zhou Y.
      • Wang J.
      • Feng Y.
      • Wang H.
      • Xue J.
      • Chen Y.
      • Ye R.D.
      • Wang M.W.
      V101L of human formyl peptide receptor 1 (FPR1) increases receptor affinity and augments the antagonism mediated by cyclosporins.
       Monocytes
      • Crouser E.D.
      • Shao G.
      • Julian M.W.
      • Macre J.E.
      • Shadel G.S.
      • Tridandapani S.
      • Huang Q.
      • Wewers M.D.
      Monocyte activation by necrotic cells is promoted by mitochondrial proteins and formyl peptide receptors.
      Cathepsin G
      • Sun R.
      • Iribarren P.
      • Zhang N.
      • Zhou Y.
      • Gong W.
      • Cho E.H.
      • Lockett S.
      • Chertov O.
      • Bednar F.
      • Rogers T.J.
      • Oppenheim J.J.
      • Wang J.M.
      Identification of neutrophil granule protein cathepsin G as a novel chemotactic agonist for the G protein-coupled formyl peptide receptor.
      Boc-MLF (Boc-1)
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Dendritic cells
      • Kang H.K.
      • Lee H.Y.
      • Kim M.K.
      • Park K.S.
      • Park Y.M.
      • Kwak J.Y.
      • Bae Y.S.
      The synthetic peptide Trp-Lys-Tyr-Met-Val-D-Met inhibits human monocyte-derived dendritic cell maturation via formyl peptide receptor and formyl peptide receptor-like 2.
      FAM19A4
      • Wang W.
      • Li T.
      • Wang X.
      • Yuan W.
      • Cheng Y.
      • Zhang H.
      • Xu E.
      • Zhang Y.
      • Shi S.
      • Ma D.
      • Han W.
      FAM19A4 is a novel cytokine ligand of formyl peptide receptor 1 (FPR1) and is able to promote the migration and phagocytosis of macrophages.
      Boc-FLFLFL (Boc 2)
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Epithelial cells
      • Leoni G.
      • Alam A.
      • Neumann P.A.
      • Lambeth J.D.
      • Cheng G.
      • McCoy J.
      • Hilgarth R.S.
      • Kundu K.
      • Murthy N.
      • Kusters D.
      • Reutelingsperger C.
      • Perretti M.
      • Parkos C.A.
      • Neish A.S.
      • Nusrat A.
      Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.
      Annexin A1
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.
      • Leoni G.
      • Alam A.
      • Neumann P.A.
      • Lambeth J.D.
      • Cheng G.
      • McCoy J.
      • Hilgarth R.S.
      • Kundu K.
      • Murthy N.
      • Kusters D.
      • Reutelingsperger C.
      • Perretti M.
      • Parkos C.A.
      • Neish A.S.
      • Nusrat A.
      Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.
      CHIPS
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
       Hepatocytes
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      Ac2-26
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.
      • Leoni G.
      • Alam A.
      • Neumann P.A.
      • Lambeth J.D.
      • Cheng G.
      • McCoy J.
      • Hilgarth R.S.
      • Kundu K.
      • Murthy N.
      • Kusters D.
      • Reutelingsperger C.
      • Perretti M.
      • Parkos C.A.
      • Neish A.S.
      • Nusrat A.
      Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.
      Spinorphin
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
       Glial cells
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Astrocytes
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Keratinocytes
      • Saito N.
      • Qiao H.
      • Yanagi T.
      • Shinkuma S.
      • Nishimura K.
      • Suto A.
      • Fujita Y.
      • Suzuki S.
      • Nomura T.
      • Nakamura H.
      • Nagao K.
      • Obuse C.
      • Shimizu H.
      • Abe R.
      An annexin A1–FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions.
      FPR2
       Neutrophils
      • Bozinovski S.
      • Anthony D.
      • Anderson G.P.
      • Irving L.B.
      • Levy B.D.
      • Vlahos R.
      Treating neutrophilic inflammation in COPD by targeting ALX/FPR2 resolution pathways.
      N-formylated peptides
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR.
      Boc-MLF (Boc-1)
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Macrophages
      • Li Y.
      • Cai L.
      • Wang H.
      • Wu P.
      • Gu W.
      • Chen Y.
      • Hao H.
      • Tang K.
      • Yi P.
      • Liu M.
      • Miao S.
      • Ye D.
      Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2.
      fMLF
      • He H.Q.
      • Troksa E.L.
      • Caltabiano G.
      • Pardo L.
      • Ye R.D.
      Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands.
      Boc-FLFLFL (Boc 2)
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Monocytes
      • Wan M.
      • Godson C.
      • Guiry P.J.
      • Agerberth B.
      • Haeggström J.Z.
      Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1.
      LL-37
      • Wan M.
      • Godson C.
      • Guiry P.J.
      • Agerberth B.
      • Haeggström J.Z.
      Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1.
      WRW4 peptide
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Dendritic cells
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
      Serum amyloid A
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
       Microglia
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
      β-Amyloid
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
       T lymphocytes
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
      HIV gp41-derived peptide
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
       Epithelial cells
      • Leoni G.
      • Alam A.
      • Neumann P.A.
      • Lambeth J.D.
      • Cheng G.
      • McCoy J.
      • Hilgarth R.S.
      • Kundu K.
      • Murthy N.
      • Kusters D.
      • Reutelingsperger C.
      • Perretti M.
      • Parkos C.A.
      • Neish A.S.
      • Nusrat A.
      Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.
      Annexin A1
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.
      • Cooray S.N.
      • Gobbetti T.
      • Montero-Melendez T.
      • McArthur S.
      • Thompson D.
      • Clark A.J.
      • Flower R.J.
      • Perretti M.
      Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses.
      Ac2-26
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.
      • Cooray S.N.
      • Gobbetti T.
      • Montero-Melendez T.
      • McArthur S.
      • Thompson D.
      • Clark A.J.
      • Flower R.J.
      • Perretti M.
      Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses.
      Lipoxin A4
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.
      • Wan M.
      • Godson C.
      • Guiry P.J.
      • Agerberth B.
      • Haeggström J.Z.
      Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1.
      Humanin
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.
      • Harada M.
      • Habata Y.
      • Hosoya M.
      • Nishi K.
      • Fujii R.
      • Kobayashi M.
      • Hinuma S.
      N-Formylated humanin activates both formyl peptide receptor-like 1 and 2.
      FPR3
       Macrophages
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      F2L
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.
      • Devosse T.
      • Dutoit R.
      • Migeotte I.
      • De Nadai P.
      • Imbault V.
      • Communi D.
      • Salmon I.
      • Parmentier M.
      Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3.
      WRW4 peptide
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Monocytes
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      Humanin
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.
      • Harada M.
      • Habata Y.
      • Hosoya M.
      • Nishi K.
      • Fujii R.
      • Kobayashi M.
      • Hinuma S.
      N-Formylated humanin activates both formyl peptide receptor-like 1 and 2.
       Dendritic cells
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
       Eosinophils
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
      Ac2-26, N-terminal peptide of annexin 1; Boc-FLFLFL, Boc-Phe-Leu-Phe-Leu-Phe-OH; Boc-MLF, Boc-Met-Leu-Phe-OH; CHIPS, chemotaxis inhibitory protein of Staphylococcus aureus; FAM19A4, family with sequence similarity 19, member A4; fMLF, formyl-methyl-leucine-phenylalanine; FPR, formyl peptide receptor; gp, glycoprotein; LL-37, leucine, leucine 37; WRW4, Trp-Arg-Trp-Trp-Trp-Trp-CONH2 (WRWWWW).
      Anti-inflammatory agonist; the ligands described elicit functional responses in a number of cell types.

      FPR1 Binding Properties

      Much is known about the structure and function of FPR1 at a molecular level and its interaction with the Escherichia coli–derived prototypic synthetic ligand fMLF. Firstly, the formyl group at the N-terminus allows hydrogen bond formation to a hydrogen acceptor within the binding pocket. Secondly, the methionine side chain may occupy a hydrophobic pocket within the receptor, with the sulfur atom in the ligand interacting with a positively charged portion of the receptor. Finally, further hydrophobic interactions may occur between the leucine and phenylalanine residues and FPR1.
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      After binding to FPR1, fMLF is internalized within approximately 30 seconds and stimulates a variety of intracellular signaling cascades, resulting in a number of cellular responses. Within neutrophils, these include chemotaxis, ROS production, degranulation, cytokine expression, phagocytosis, and changes in cell surface marker expression.
      • Prossnitz E.R.
      • Ye R.D.
      The N-formyl peptide receptor: a model for the study of chemoattractant receptor structure and function.
      • Dorward D.A.
      • Lucas C.D.
      • Alessandri A.L.
      • Marwick J.A.
      • Rossi F.
      • Dransfield I.
      • Haslett C.
      • Dhaliwal K.
      • Rossi A.G.
      Technical advance: autofluorescence-based sorting: rapid and nonperturbing isolation of ultrapure neutrophils to determine cytokine production.
      • Liu M.
      • Chen K.
      • Yoshimura T.
      • Liu Y.
      • Gong W.
      • Wang A.
      • Gao J.L.
      • Murphy P.M.
      • Wang J.M.
      Formylpeptide receptors are critical for rapid neutrophil mobilization in host defense against Listeria monocytogenes.

      FPR1 Desensitization

      As discussed, regulation of GPCR function is essential in vivo for controlling neutrophil functions, including chemotaxis and the exact localization of cells to the inflammatory site.
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
      • Prossnitz E.R.
      • Ye R.D.
      The N-formyl peptide receptor: a model for the study of chemoattractant receptor structure and function.
      • Heit B.
      • Robbins S.M.
      • Downey C.M.
      • Guan Z.
      • Colarusso P.
      • Miller B.J.
      • Jirik F.R.
      • Kubes P.
      PTEN functions to ‘prioritize' chemotactic cues and prevent ‘distraction' in migrating neutrophils.
      After FPR1-ligand binding, the cell rapidly becomes unresponsive to subsequent stimulation by the same ligand (homologous desensitization). Multiple distinct processes account for this change in cell function, including receptor internalization and desensitization.
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      The latter is mediated by phosphorylation of multiple serine and threonine residues within the carboxy-terminal, leading to G-protein dissociation and disruption of intracellular signaling pathways, a process that is governed in part by ERK1/2–GPCR kinase 2 (GPK2) and arrestin binding.
      • Liu X.
      • Ma B.
      • Malik A.B.
      • Tang H.
      • Yang T.
      • Sun B.
      • Wang G.
      • Minshall R.D.
      • Li Y.
      • Zhao Y.
      • Ye R.D.
      • Xu J.
      Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases.
      • Maaty W.S.
      • Lord C.I.
      • Gripentrog J.M.
      • Riesselman M.
      • Keren-Aviram G.
      • Liu T.
      • Dratz E.A.
      • Bothner B.
      • Jesaitis A.J.
      Identification of C-terminal phosphorylation sites of N-formyl peptide receptor-1 (FPR1) in human blood neutrophils.
      Meanwhile, receptor internalization predominantly occurs after C-terminal phosphorylation through β-arrestin–independent and non–clathrin-mediated endocytosis.
      • Ye R.D.
      • Boulay F.
      • Wang J.M.
      • Dahlgren C.
      • Gerard C.
      • Parmentier M.
      • Serhan C.N.
      • Murphy P.M.
      International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
      • Xue M.
      • Hsieh G.
      • Raymond-Stintz M.A.
      • Pfeiffer J.
      • Roberts D.
      • Steinberg S.L.
      • Oliver J.M.
      • Prossnitz E.R.
      • Lidke D.S.
      • Wilson B.S.
      Activated N-formyl peptide receptor and high-affinity IgE receptor occupy common domains for signaling and internalization.
      Heterologous desensitization of FPR1 can also occur after activation of CD88 [a complement component 5a (C5a) receptor] or chemokine (C-X-C motif) receptor 2 CXCR2; (an IL-8 receptor) due to shared components of intracellular signaling molecules and occurs principally through protein kinase C–mediated pathways.
      • Ali H.
      • Richardson R.M.
      • Haribabu B.
      • Snyderman R.
      Chemoattractant receptor cross-desensitization.
      Due to the intracellular signaling hierarchy that exists, however, the capacity for FPR1's heterologous desensitization of other receptors far outstrips their reciprocal ability to inhibit FPR1 function,
      • Heit B.
      • Tavener S.
      • Raharjo E.
      • Kubes P.
      An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients.
      which was recently highlighted by the observation that the activation of FPR1 in monocytes induces cross-desensitization of CCR1 but not CCR2.
      • Heit B.
      • Tavener S.
      • Raharjo E.
      • Kubes P.
      An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients.
      This observation suggests the ability of FPR1 to act as a regulator of chemoreceptor hierarchy with regard to prioritizing not only its own signaling but also that of other potent and important agonists, such as those that bind CCR2.
      • Bednar F.
      • Song C.
      • Bardi G.
      • Cornwell W.
      • Rogers T.J.
      Cross-desensitization of CCR1, but not CCR2, following activation of the formyl peptide receptor FPR1.
      Importantly, these reductions in cell surface receptor number and function can be relatively short-lived, as receptor and ligand dissociate from each other after internalization and the receptor returns to the cell surface available for further ligand binding.

      Intracellular Signaling

      Characterization of the FPR1 signaling cascades has been conducted with fMLF as the stereotypical ligand and has revealed a highly complex and integrated chain of intracellular signaling events.
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      • Prossnitz E.R.
      • Ye R.D.
      The N-formyl peptide receptor: a model for the study of chemoattractant receptor structure and function.
      Binding to FPR1 results in Gi-type G-protein activation, with the conversion of GDP to GTP inducing the dissociation of α from the βγ subunits (Figure 2). The latter liberated subunits activate both the phospholipase Cβ and phosphoinositide 3-kinase γ (PI3Kγ) signaling cascades. Phospholipase Cβ hydrolyses membrane-bound phosphoinositol-4,5-bisphosphate into diacylglycerol and inositol trisphosphate to mediate the release of intracellular calcium stores, principally from the endoplasmic reticulum. These events subsequently activate protein kinase C and are central to NADPH oxidase ROS production.
      • O’Flaherty J.T.
      • Jacobson D.P.
      • Redman J.F.
      • Rossi A.G.
      Translocation of protein kinase C in human polymorphonuclear neutrophils. Regulation by cytosolic Ca2(+)-independent and Ca2(+)-dependent mechanisms.
      Meanwhile, PI3Kγ-mediated conversion of phosphoinositol-4,5-bisphosphate to phosphoinositol-3,4,5-trisphosphate acts as the principal regulator of neutrophil cytoskeletal reorganization and respiratory burst after FPR1 activation as well as influences the chemotactic response.
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      • Heit B.
      • Robbins S.M.
      • Downey C.M.
      • Guan Z.
      • Colarusso P.
      • Miller B.J.
      • Jirik F.R.
      • Kubes P.
      PTEN functions to ‘prioritize' chemotactic cues and prevent ‘distraction' in migrating neutrophils.
      Figure thumbnail gr2
      Figure 2Intracellular signaling events after FPR1 receptor activation. After binding of ligand to formyl peptide receptor 1 (FPR1), conversion of guanosine diphosphate to guanosine triphosphate induces dissociation of the α from the βγ subunits. These trigger a range of intracellular kinase pathways, resulting in the induction of a variety of cell functions, including neutrophil chemotaxis, degranulation, superoxide anion production, and transcriptional activity. The predominant signaling pathways are those of phosphoinositide-3 kinase (PI3K), mitogen-activated protein kinase (MAPK), and phospholipase C. The latter triggers release of intracellular calcium from the endoplasmic reticulum to activate protein kinase C (PKC) and subsequent reactive oxygen species production, whereas PI3K triggers protein kinase B (alias Akt)-mediated and phosphoinositol-3,4,5-trisphosphate (PIP3)-mediated signaling, with a variety of cellular effects. With PI3K pulled toward the plasma membrane by the β and γ G-protein subunits (Gβ and Gγ), activation of Ras family proteins and MAPK further contributes to oxidative burst and chemotaxis. CDC, cell division control protein; DAG, diacyl glycerol; Gα, G-protein α; GEF, guanine nucleotide exchange factor; Grb, growth factor receptor–bound protein; IP3, inositol trisphosphate; MEKK, mitogen-activated protein kinase kinase; PA, phosphatidic acid; PLCβ, phospholipase Cβ; PLD, phospholipase D; RAF, rapidly accelerated fibrosarcoma; Sos, son of sevenless; WASP, Wiskott-Aldrich syndrome protein.
      As the βγ subunits activate PI3Kγ and pull it toward the plasma membrane, the activity of Src-like tyrosine kinases increases with the phosphorylation of the Src homology 2 domain–containing (Shc) adaptor protein, which, in turn, increases the association with growth factor receptor–bound protein 2 and son of sevenless and subsequently activates MAPK signaling pathways. ERK and p38 MAPK predominantly influence chemotaxis and FPR1-mediated transcriptional activity.
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview.
      Meanwhile, the activation of guanine–nucleotide exchange factors induces the activation of the Rho GTPases [Rho, Rac, and cell division control protein 42 (CDC42)]. These, in turn, regulate ROS production through control of the formation of NADPH oxidase complex
      • Ye R.D.
      • Boulay F.
      • Wang J.M.
      • Dahlgren C.
      • Gerard C.
      • Parmentier M.
      • Serhan C.N.
      • Murphy P.M.
      International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
      as well as influence leukocyte adhesion, transmigration, actin polymerization, and phagocytosis.
      • Morris A.C.
      • Brittan M.
      • Wilkinson T.S.
      • McAuley D.F.
      • Antonelli J.
      • McCulloch C.
      • Barr L.C.
      • McDonald N.A.
      • Dhaliwal K.
      • Jones R.O.
      • Mackellar A.
      • Haslett C.
      • Hay A.W.
      • Swann D.G.
      • Anderson N.
      • Laurenson I.F.
      • Davidson D.J.
      • Rossi A.G.
      • Walsh T.S.
      • Simpson A.J.
      C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients.
      Although much of this work is well recognized, recent work using antibodies specific to C-terminal phosphorylation sites within the FPR1 protein has demonstrated that in some cases, in particular in the context of inflammatory bowel disease, G-protein–insensitive, formylated peptide–dependent FPR1 phosphorylation may also occur. This observation was noted to be predominantly at the surface of colonic crypt abscesses, leading Leoni et al
      • Leoni G.
      • Gripentrog J.
      • Lord C.
      • Riesselman M.
      • Sumagin R.
      • Parkos C.A.
      • Nusrat A.
      • Jesaitis A.J.
      Human neutrophil formyl peptide receptor phosphorylation and the mucosal inflammatory response.
      to postulate that this possible reactivation of FPR1 at distinct sites of inflammation may contribute to perpetuation of the acute and often deleterious inflammatory response.
      New facets of the conventional understanding of FPR1 signaling within neutrophils have begun to emerge in recent years, for example, the appreciation of its interconnection with autocrine release of ATP and subsequent purinergic signaling. Recent work by Bao et al
      • Bao Y.
      • Ledderose C.
      • Seier T.
      • Graf A.F.
      • Brix B.
      • Chong E.
      • Junger W.G.
      Mitochondria regulate neutrophil activation by generating ATP for autocrine purinergic signaling.
      demonstrated that FPR1 signaling induces a rapid, but reversible, increase in the mitochondrial membrane potential within neutrophils, with an associated oxidative burst and extracellular release of ATP through pannexin 1 channels. Despite the conventional understanding that neutrophil-mediated ATP production occurs through glycolysis, researchers demonstrate that the initial burst of ATP is mitochondria derived and important in initiating the FPR/purinergic response. The autocrine ATP appears to then bind purinergic P2Y2 and P2X receptors to augment neutrophil chemotaxis, intracellular calcium flux, and p38 and ERK p42/44 MAPK signaling but appears to have little effect on fMLF-mediated degranulation and phagocytosis. Interestingly, pannexin 1 channels and the purinergic receptors accumulate at the leading edge of the polarized neutrophil, providing opportunity for coordinated migratory activity.
      • Bao Y.
      • Ledderose C.
      • Seier T.
      • Graf A.F.
      • Brix B.
      • Chong E.
      • Junger W.G.
      Mitochondria regulate neutrophil activation by generating ATP for autocrine purinergic signaling.
      • Chen Y.
      • Corriden R.
      • Inoue Y.
      • Yip L.
      • Hashiguchi N.
      • Zinkernagel A.
      • Nizet V.
      • Insel P.A.
      • Junger W.G.
      ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors.
      • Bao Y.
      • Chen Y.
      • Ledderose C.
      • Li L.
      • Junger W.G.
      Pannexin 1 channels link chemoattractant receptor signaling to local excitation and global inhibition responses at the front and back of polarized neutrophils.
      Also, localizing to the leading edge of the migrating neutrophil is the receptor of urokinase-type plasminogen activator serine protease to facilitate urokinase-type plasminogen activator–mediated degradation of the extracellular matrix, thus allowing for extravascular neutrophil transit. It is understood that urokinase-type plasminogen activator receptor expression is necessary for fMLF-induced chemotaxis through a variety of means, including the colocalization of FPR1 and β1-integrins at the cell surface, with urokinase-type plasminogen activator receptor acting as a bridging molecule to facilitate their respective functions.
      • Gorrasi A.
      • Li Santi A.
      • Amodio G.
      • Alfano D.
      • Remondelli P.
      • Montuori N.
      • Ragno P.
      The urokinase receptor takes control of cell migration by recruiting integrins and FPR1 on the cell surface.
      These novel observations, therefore, provide further insight into the highly regulated and integrated crosstalk between different ligands and their receptors in fine-tuning the functional response to inflammatory agents.

      Formyl Peptide Receptor 2

      In contrast to the specificity of FPR1, its relative FPR2/ALX is a highly promiscuous receptor that binds fMLF with low affinity.
      • He H.Q.
      • Troksa E.L.
      • Caltabiano G.
      • Pardo L.
      • Ye R.D.
      Structural determinants for the interaction of formyl peptide receptor 2 with peptide ligands.
      It was one of the first descriptions of a receptor capable of binding lipids, peptides, and proteins with ligands including serum amyloid A, lipoxin A4, and AnnA1 and has been reviewed in detail elsewhere.
      • Dufton N.
      • Perretti M.
      Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists.
      • Bozinovski S.
      • Anthony D.
      • Anderson G.P.
      • Irving L.B.
      • Levy B.D.
      • Vlahos R.
      Treating neutrophilic inflammation in COPD by targeting ALX/FPR2 resolution pathways.
      • Yang Y.H.
      • Morand E.
      • Leech M.
      Annexin A1: potential for glucocorticoid sparing in RA.
      Importantly, these ligand-specific interactions are able to induce either proinflammatory or proresolution/anti-inflammatory effects. With regard to binding to formylated peptides, the binding affinity of FPR2 is determined principally by the charge of the C-terminus of peptide, contrary to FPR1 which, as discussed in FPR1 Ligands, is N-terminal dependent.
      Binding of serum amyloid A or the cathelicidin-associated antimicrobial peptide leucine, leucine-37 (LL37) to FPR2/ALX results in proinflammatory responses with neutrophil NF-κB activation and cytokine release, increased neutrophil recruitment to sites of inflammation, and increased neutrophil lifespan.
      • Wan M.
      • Godson C.
      • Guiry P.J.
      • Agerberth B.
      • Haeggström J.Z.
      Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1.
      • El Kebir D.
      • József L.
      • Khreiss T.
      • Pan W.
      • Petasis N.A.
      • Serhan C.N.
      • Filep J.G.
      Aspirin-triggered lipoxins override the apoptosis-delaying action of serum amyloid A in human neutrophils: a novel mechanism for resolution of inflammation.
      In contrast, binding of AnnA1 inhibits neutrophil migration, promotes neutrophil apoptosis, increases the rate of macrophage phagocytosis of apoptotic cells, and skews the macrophages toward a less proinflammatory phenotype.
      • Li Y.
      • Cai L.
      • Wang H.
      • Wu P.
      • Gu W.
      • Chen Y.
      • Hao H.
      • Tang K.
      • Yi P.
      • Liu M.
      • Miao S.
      • Ye D.
      Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2.
      Lipoxin A4, again through FPR2/ALX, inhibits neutrophil migration while concomitantly augmenting monocyte recruitment. These distinct effects elicited from ligand binding to the same receptor have recently been attributed to different dimerization states after agonist binding that alter receptor conformation and subsequent intracellular signaling.
      • Cooray S.N.
      • Gobbetti T.
      • Montero-Melendez T.
      • McArthur S.
      • Thompson D.
      • Clark A.J.
      • Flower R.J.
      • Perretti M.
      Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses.

      Formyl Peptide Receptor 3

      Distinct from the other members of the FPR family, the function of FPR3 remains relatively poorly understood. While not expressed on human neutrophils, it is found in eosinophils, monocytes, macrophages, and dendritic cells, leading to speculation that it may play a role in the pathogenesis of allergic disease.
      • Devosse T.
      • Guillabert A.
      • D'Haene N.
      • Berton A.
      • De Nadai P.
      • Noel S.
      • Brait M.
      • Franssen J.D.
      • Sozzani S.
      • Salmon I.
      • Parmentier M.
      Formyl peptide receptor-like 2 is expressed and functional in plasmacytoid dendritic cells, tissue-specific macrophage subpopulations, and eosinophils.
      FPR3 is relatively insensitive to formylated peptides, and few specific endogenous ligands have been identified. F2L, an endogenous 21–amino acid acetylated amino-terminal peptide, is the most specific ligand described to date.
      • Migeotte I.
      • Riboldi E.
      • Franssen J.D.
      • Grégoire F.
      • Loison C.
      • Wittamer V.
      • Detheux M.
      • Robberecht P.
      • Costagliola S.
      • Vassart G.
      • Sozzani S.
      • Parmentier M.
      • Communi D.
      Identification and characterization of an endogenous chemotactic ligand specific for FPRL2.
      Derived from cleavage of heme-binding protein 1 by cathepsin D, F2L activates FPR3 in low nanomolar concentrations.
      • Devosse T.
      • Dutoit R.
      • Migeotte I.
      • De Nadai P.
      • Imbault V.
      • Communi D.
      • Salmon I.
      • Parmentier M.
      Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3.
      In doing so, it induces monocyte intracellular calcium flux, ERK1/2 phosphorylation, and chemotaxis while also augmenting LPS-mediated IL-12 production in dendritic cells, thereby inhibiting their maturation.
      • Kang H.K.
      • Lee H.Y.
      • Kim M.K.
      • Park K.S.
      • Park Y.M.
      • Kwak J.Y.
      • Bae Y.S.
      The synthetic peptide Trp-Lys-Tyr-Met-Val-D-Met inhibits human monocyte-derived dendritic cell maturation via formyl peptide receptor and formyl peptide receptor-like 2.
      • Migeotte I.
      • Riboldi E.
      • Franssen J.D.
      • Grégoire F.
      • Loison C.
      • Wittamer V.
      • Detheux M.
      • Robberecht P.
      • Costagliola S.
      • Vassart G.
      • Sozzani S.
      • Parmentier M.
      • Communi D.
      Identification and characterization of an endogenous chemotactic ligand specific for FPRL2.
      Humanin, a neuroprotective peptide, also binds with high affinity to both FPR2 and FPR3.
      • Harada M.
      • Habata Y.
      • Hosoya M.
      • Nishi K.
      • Fujii R.
      • Kobayashi M.
      • Hinuma S.
      N-Formylated humanin activates both formyl peptide receptor-like 1 and 2.
      Despite the high sequence homology with FPR2/ALX, the behavior of FPR3 is surprising, with significantly higher basal levels of receptor phosphorylation and internalization and relative insensitivity to common FPR2/ALX ligands.
      • Rabiet M.J.
      • Macari L.
      • Dahlgren C.
      • Boulay F.
      N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation.
      This observation has led to the hypothesis that it may also act as a decoy receptor to bind extracellular ligands, thereby regulating the function of other formylated peptide receptors.
      • Rabiet M.J.
      • Macari L.
      • Dahlgren C.
      • Boulay F.
      N-formyl peptide receptor 3 (FPR3) departs from the homologous FPR2/ALX receptor with regard to the major processes governing chemoattractant receptor regulation, expression at the cell surface, and phosphorylation.
      Although there is likely to be some functional overlap with FPR2/ALX, the true functional role of FPR3 and its relevance in vivo remain to be determined.

      Mouse FPR Receptors

      FPR1 has been described across several species, including horse, rabbits, and rodents, with marked differences in functional responses to formylated peptides observed.
      • Ye R.D.
      • Boulay F.
      • Wang J.M.
      • Dahlgren C.
      • Gerard C.
      • Parmentier M.
      • Serhan C.N.
      • Murphy P.M.
      International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
      In comparison to the three FPR receptors described in humans, the mouse genome encodes multiple FPR-related receptors from chromosome 17A3.2.
      • Tiffany H.L.
      • Gao J.L.
      • Roffe E.
      • Sechler J.M.
      • Murphy P.M.
      Characterization of Fpr-rs8, an atypical member of the mouse formyl peptide receptor gene family.
      Fpr1 is the murine orthologue of human FPR1, sharing 77% homology, expression on similar cell types, and induction of the same effects of neutrophil chemotaxis, degranulation, cytokine production, and phagocytosis.
      • Gao J.L.
      • Chen H.
      • Filie J.D.
      • Kozak C.A.
      • Murphy P.M.
      Differential expansion of the N-formylpeptide receptor gene cluster in human and mouse.
      Genes Fpr2 and Fpr3 together encode receptors that mimic human FPR2/ALX. Fpr2 encodes the ALX receptor specific for lipoxin A4, whereas Fpr3 encodes Fpr2, which binds formylated peptides, serum amyloid A, and other similar ligands.
      • Ye R.D.
      • Boulay F.
      • Wang J.M.
      • Dahlgren C.
      • Gerard C.
      • Parmentier M.
      • Serhan C.N.
      • Murphy P.M.
      International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family.
      Similarities between murine Fpr2 and human FPR3 with regard to responsiveness to F2L have also been observed.
      • He H.Q.
      • Liao D.
      • Wang Z.G.
      • Wang Z.L.
      • Zhou H.C.
      • Wang M.W.
      • Ye R.D.
      Functional characterization of three mouse formyl peptide receptors.
      At present, the function and cognate ligands of the remaining murine Fpr receptors are poorly characterized and understood. Fpr-related sequences 3, 4, 6, and 7 may function as chemoreceptors in vomeronasal olfactory sensory neurons,
      • Rivière S.
      • Challet L.
      • Fluegge D.
      • Spehr M.
      • Rodriguez I.
      Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors.
      whereas Fpr-related sequence 8 appears to affect the lifespan of mice, although the reason for this remains unknown at present.
      • Tiffany H.L.
      • Gao J.L.
      • Roffe E.
      • Sechler J.M.
      • Murphy P.M.
      Characterization of Fpr-rs8, an atypical member of the mouse formyl peptide receptor gene family.
      Although there is relatively high sequence homology of FPR1 between humans and mice, and the intracellular domain structure is highly conserved, there are distinct differences in the affinity of murine Fpr1 for fMLF, which is approximately 100-fold less than that of its human counterpart.
      • He H.Q.
      • Liao D.
      • Wang Z.G.
      • Wang Z.L.
      • Zhou H.C.
      • Wang M.W.
      • Ye R.D.
      Functional characterization of three mouse formyl peptide receptors.
      This difference in affinity is attributed to alterations in the folding of the transmembrane and extracellular domains, as determined by the apposition of multiple noncontiguous residues.
      • Gao J.L.
      • Murphy P.M.
      Species and subtype variants of the N-formyl peptide chemotactic receptor reveal multiple important functional domains.
      Although differences in the affinity of a receptor to prototypic E. coli–derived fMLF are described, it should be noted that, with regard to other bacterial formylated peptides, murine Fpr1 remains a high-affinity receptor, in particular to Staphylococcus aureus, Listeria monocytogenes, and mitochondria-derived formylated peptides.
      • He H.Q.
      • Liao D.
      • Wang Z.G.
      • Wang Z.L.
      • Zhou H.C.
      • Wang M.W.
      • Ye R.D.
      Functional characterization of three mouse formyl peptide receptors.
      Although it is important to be aware of such differences, inferences from mouse models of disease remain relevant and have, to date, significantly advanced our understanding of FPR biology and neutrophil function in both the physiological and pathophysiological states.

      FPR1 in Health and Disease

      Mitochondrial Formylated Peptides

      With regard to neutrophil FPR1 function, the principal proinflammatory effects are mediated through bacterial and mitochondrial formylated peptides. Given the increasing interest in the role of FPR1 in sterile inflammation, we focus on the synthesis, release, and function of the latter in greater detail. It has been proposed that mitochondria arose over 2 billion years ago after the inclusion of α-proteobacteria within the ancient precursors of eukaryotic cells. Much of the initial genetic material contained within these bacteria has either been lost or transferred to the nuclear genome, which now encodes the vast majority of the approximately 1500 mitochondrial proteins.
      • Taylor S.W.
      • Fahy E.
      • Ghosh S.S.
      Global organellar proteomics.
      What has been left, however, is approximately 16 Kb of CpG-rich, unmethylated mitochondrial DNA (mtDNA), which encodes for 13 mitochondrial peptides that make up the key components of the respiratory chain within the inner mitochondrial membrane. In addition, mtDNA also contains coding information of 22 tRNAs and two mitochondrial ribosome (mitoribosome)-coding RNAs, vital for the processes of translation and peptide synthesis.
      • Taanman J.W.
      The mitochondrial genome: structure, transcription, translation and replication.
      Distinct from eukaryotic cytoplasmic ribosomes, prokaryotic and mitochondrial protein synthesis require an N-terminal fMet residue to initiate translation. Mitoribosomes are located in the mitochondrial matrix, with approximately 100 per organelle, and contain 39S and 28S ribosomal subunits.
      • Taanman J.W.
      The mitochondrial genome: structure, transcription, translation and replication.
      Unlike cytoplasmic mRNA, mitochondrial mRNA has no upstream leader sequence to coordinate mitoribosome binding but instead starts at the 5′ end, with the N-terminal fMet binding to the mRNA start codon. N-terminal fMet binding to the small (28S) ribosome is facilitated by mitochondrial translational initiation factor 2 in a GTP-dependent process. Importantly, it is only N-terminal fMet and not Met-tRNA that is recognized by mitochondrial translational initiation factor 2 as the initiator tRNA, hence the crucial and irreplaceable nature of fMet in mitochondrial peptide synthesis.
      • Spencer A.C.
      • Spremulli L.L.
      Interaction of mitochondrial initiation factor 2 with mitochondrial fMet-tRNA.
      Although extracellular mitochondrial formylated peptides are recognized as potent damage-associated molecular patterns, within mitochondria they are naturally subjected to post-translational modification. Some peptides, however, undergo removal of the formyl group which principally occurs through the action of peptide deformylase, a zinc- and iron-binding metalloproteinase that hydrolytically cleaves the N-terminal formyl moiety.
      • Becker A.
      • Schlichting I.
      • Kabsch W.
      • Groche D.
      • Schultz S.
      • Wagner A.F.
      Iron center, substrate recognition and mechanism of peptide deformylase.
      Inhibition of peptide deformylase causes a global reduction in the accumulation of mtDNA-encoded proteins, with impaired subsequent assembly of components of the respiratory chain and therefore mitochondrial energy production.
      • Escobar-Alvarez S.
      • Gardner J.
      • Sheth A.
      • Manfredi G.
      • Yang G.
      • Ouerfelli O.
      • Heaney M.L.
      • Scheinberg D.A.
      Inhibition of human peptide deformylase disrupts mitochondrial function.
      Despite these observations, the exact role and contribution of peptide deformylase and the balance between mature formylated and deformylated peptides within the mitochondria remain poorly understood. Importantly, it appears that peptide deformylase is not capable of deformylating all mitochondria-synthesized peptides.
      • Escobar-Alvarez S.
      • Goldgur Y.
      • Yang G.
      • Ouerfelli O.
      • Li Y.
      • Scheinberg D.A.
      Structure and activity of human mitochondrial peptide deformylase, a novel cancer target.
      Indeed, deformylation does not completely remove the presence of formylated peptides within eukaryotic cells, as both formylated and deformylated versions of the same peptides coexist.
      • Escobar-Alvarez S.
      • Gardner J.
      • Sheth A.
      • Manfredi G.
      • Yang G.
      • Ouerfelli O.
      • Heaney M.L.
      • Scheinberg D.A.
      Inhibition of human peptide deformylase disrupts mitochondrial function.
      It is also interesting to note that extracellular deformylase enzymes within rat intestinal mucosa that sequentially cleave bacterial formylated peptides to reduce the abundance of proinflammatory mediators have been described.
      • Nguyen K.T.
      • Pei D.
      Purification and characterization of enzymes involved in the degradation of chemotactic N-formyl peptides.
      At present, there is no direct evidence of active release of mitochondrial formylated peptides from cells; rather, it is considered a passive process after necrotic cell death. This method of release is obviously distinct from bacteria, which can actively secrete formylated peptides into the extracellular milieu.
      • Karlsson A.
      • Markfjall M.
      • Stromberg N.
      • Dahlgren C.
      Escherichia coli-induced activation of neutrophil NADPH-oxidase: lipopolysaccharide and formylated peptides act synergistically to induce release of reactive oxygen metabolites.
      Given the description of autophagy-mediated high-mobility group box protein 1 (HMGB1), IL-1β, mtDNA, and ATP release, it is not inconceivable that formylated peptides are also actively released by similar mechanisms.
      • Zhang Q.
      • Kang R.
      • Zeh 3rd, H.J.
      • Lotze M.T.
      • Tang D.
      DAMPs and autophagy: cellular adaptation to injury and unscheduled cell death.

      FPR1 in Sterile Inflammation

      The importance of mitochondrial formylated peptides in influencing neutrophil function was originally described by Carp,
      • Carp H.
      Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils.
      who demonstrated their ability in vitro, distinct from nonformylated mitochondrial proteins, to induce neutrophil chemotaxis through binding to FPR1. This finding was substantiated by the subsequent demonstration of their ability to induce neutrophil-like promyelocytic HL-60 cell intracellular calcium flux and superoxide anion production through binding to both FPR1 and FPR2/ALX.
      • Rabiet M.J.
      • Huet E.
      • Boulay F.
      Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR.
      Further appreciation of their in vivo significance as important damage-associated molecular patterns came with the description of elevated mtDNA levels, as a general marker of liberated mitochondrial products, in the circulation of patients with aseptic, trauma-induced systemic inflammatory response syndrome.
      • Zhang Q.
      • Raoof M.
      • Chen Y.
      • Sumi Y.
      • Sursal T.
      • Junger W.
      • Brohi K.
      • Itagaki K.
      • Hauser C.J.
      Circulating mitochondrial DAMPs cause inflammatory responses to injury.
      Alongside this observation, Zhang et al
      • Zhang Q.
      • Raoof M.
      • Chen Y.
      • Sumi Y.
      • Sursal T.
      • Junger W.
      • Brohi K.
      • Itagaki K.
      • Hauser C.J.
      Circulating mitochondrial DAMPs cause inflammatory responses to injury.
      demonstrated the FPR1-dependent peritoneal neutrophil recruitment after i.p. injection of isolated mitochondrial damage-associated molecular patterns. Furthermore, they were able to induce alveolar neutrophil accumulation and pulmonary extravascular leak after i.v. administration of mitochondrial damage-associated molecular patterns in rats. Together with further in vitro demonstration of mitochondrial damage-associated molecular patterns–induced FPR1-dependent chemotaxis, intracellular calcium flux, and degranulation, they provided the first robust evidence of the in vivo importance of mitochondrial formylated peptide–mediated neutrophil activation and migration in driving local and distant inflammation.
      • Zhang Q.
      • Raoof M.
      • Chen Y.
      • Sumi Y.
      • Sursal T.
      • Junger W.
      • Brohi K.
      • Itagaki K.
      • Hauser C.J.
      Circulating mitochondrial DAMPs cause inflammatory responses to injury.
      • Hauser C.J.
      • Sursal T.
      • Rodriguez E.K.
      • Appleton P.T.
      • Zhang Q.
      • Itagaki K.
      Mitochondrial damage associated molecular patterns from femoral reamings activate neutrophils through formyl peptide receptors and P44/42 MAP kinase.
      • Raoof M.
      • Zhang Q.
      • Itagaki K.
      • Hauser C.J.
      Mitochondrial peptides are potent immune activators that activate human neutrophils via FPR-1.
      These findings have subsequently been supported by the discovery that, in a mouse model of paracetamol-induced liver injury in which increased levels of circulating mtDNA were detected, dual blockade of FPR1 and chemokine (C-X-C motif) receptor 2 attenuated both local hepatotoxicity and distant neutrophil migration into the lung.
      • Marques P.E.
      • Amaral S.S.
      • Pires D.A.
      • Nogueira L.L.
      • Soriani F.M.
      • Lima B.H.
      • Lopes G.A.
      • Russo R.C.
      • Avila T.V.
      • Melgaco J.G.
      • Oliveira A.G.
      • Pinto M.A.
      • Lima C.X.
      • De Paula A.M.
      • Cara D.C.
      • Leite M.F.
      • Teixeira M.M.
      • Menezes G.B.
      Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure.
      Alongside these important observations, the role of mitochondrial formylated peptides was further emphasized in eloquent work using a mouse model of focal heat–induced sterile liver injury and studied with spinning-disk intravital microscopy.
      • McDonald B.
      • Pittman K.
      • Menezes G.B.
      • Hirota S.A.
      • Slaba I.
      • Waterhouse C.C.
      • Beck P.L.
      • Muruve D.A.
      • Kubes P.
      Intravascular danger signals guide neutrophils to sites of sterile inflammation.
      After hepatic necrosis, intravascular gradients of chemokines such as macrophage inhibitory protein 2, interacting with chemokine (C-X-C motif) receptor 2, were shown to guide neutrophils crawling along the vascular endothelium to regions of sterile inflammation. Having arrived within the vascular system, neutrophils then sensed formylated peptides, exiting the capillary bed and moving through the tissue toward the area of necrosis in an FPR1-dependent manner. This observation was confirmed by the nondirectional migration of FPR1−/− neutrophils within the tissue and their failure to enter the necrotic zone, distinct from wild-type neutrophils, which rapidly accumulated within the necrotic area generated by the thermal injury.
      • McDonald B.
      • Pittman K.
      • Menezes G.B.
      • Hirota S.A.
      • Slaba I.
      • Waterhouse C.C.
      • Beck P.L.
      • Muruve D.A.
      • Kubes P.
      Intravascular danger signals guide neutrophils to sites of sterile inflammation.
      Importantly, this appears not to be an organ-specific phenomenon, as the same hierarchy of chemotactic signals was observed within areas of sterile skin inflammation even though the route of neutrophil migration was predominantly interstitial rather than intravascular.
      • Ng L.G.
      • Qin J.S.
      • Roediger B.
      • Wang Y.
      • Jain R.
      • Cavanagh L.L.
      • Smith A.L.
      • Jones C.A.
      • de Veer M.
      • Grimbaldeston M.A.
      • Meeusen E.N.
      • Weninger W.
      Visualizing the neutrophil response to sterile tissue injury in mouse dermis reveals a three-phase cascade of events.
      Understanding of the neutrophil response to infection explains the potentially significant role of mitochondrial formylated peptides in the inflammatory process. As neutrophils are essential for bacterial clearance, they need to rapidly migrate through tissues and localize invading pathogens by responding to bacteria-derived chemoattractants, including formylated peptides, and not be distracted by endogenous factors contained within the surrounding inflammatory milieu.
      • Kim D.
      • Haynes C.L.
      Neutrophil chemotaxis within a competing gradient of chemoattractants.
      The dominant role of bacterial formylated peptides, in the presence of other competing mediators, in driving neutrophil chemotaxis has been recently described.
      • Heit B.
      • Robbins S.M.
      • Downey C.M.
      • Guan Z.
      • Colarusso P.
      • Miller B.J.
      • Jirik F.R.
      • Kubes P.
      PTEN functions to ‘prioritize' chemotactic cues and prevent ‘distraction' in migrating neutrophils.
      Interstitial neutrophil migration is mediated by PI3K and p38 MAPK signaling pathways, with the latter the more dominant process. In an environment of multiple signaling mediators, neutrophil PI3K is inactivated by phosphatase and tensin homologue, allowing p38 and phospholipase A2 to drive neutrophil migration toward bacterial products.
      • Heit B.
      • Robbins S.M.
      • Downey C.M.
      • Guan Z.
      • Colarusso P.
      • Miller B.J.
      • Jirik F.R.
      • Kubes P.
      PTEN functions to ‘prioritize' chemotactic cues and prevent ‘distraction' in migrating neutrophils.
      In Pten−/− mice, this effect is lost and neutrophils fail to prioritize and become distracted by other chemokines, leading to impaired neutrophil migration with a subsequent reduction in bacterial clearance in vivo.
      • Heit B.
      • Robbins S.M.
      • Downey C.M.
      • Guan Z.
      • Colarusso P.
      • Miller B.J.
      • Jirik F.R.
      • Kubes P.
      PTEN functions to ‘prioritize' chemotactic cues and prevent ‘distraction' in migrating neutrophils.
      As mitochondrial formylated peptides appear to exert a similarly dominant hierarchical effect on neutrophil migration and function, their putative importance in the pathogenesis of sterile inflammation and tissue injury is clear.
      • Pittman K.
      • Kubes P.
      Damage-associated molecular patterns control neutrophil recruitment.

      FPR1 and Infection

      The classic description of the role of FPR1 is in the migration of neutrophils into sites of infection for the subsequent containment and killing of the microorganism. Although this role had been suggested from in vitro observations,
      • McDonald B.
      • Pittman K.
      • Menezes G.B.
      • Hirota S.A.
      • Slaba I.
      • Waterhouse C.C.
      • Beck P.L.
      • Muruve D.A.
      • Kubes P.
      Intravascular danger signals guide neutrophils to sites of sterile inflammation.
      it was the generation of the Fpr1−/− mouse that allowed for the demonstration of this role in vivo.
      • Gao J.L.
      • Lee E.J.
      • Murphy P.M.
      Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor.
      Replacement of a 150-bp sequence with a neomycin-resistance cassette of the Fpr1 gene, within the part encoding for the first extracellular loop to the fourth transmembrane domain, allowed for the complete absence of Fpr1 expression at both the protein and mRNA levels. The neutrophils were shown to be completely unresponsive to formylated peptides with regard to intracellular calcium flux as well as chemotaxis both in vitro and in vivo.
      • Gao J.L.
      • Lee E.J.
      • Murphy P.M.
      Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor.
      Injection of i.v. L. monocytogenes resulted in increased bacterial load in both the liver and spleen of Fpr1−/− mice relative to wild-type mice, attributable to reductions in neutrophil migration and diminished ROS production.
      • Liu M.
      • Chen K.
      • Yoshimura T.
      • Liu Y.
      • Gong W.
      • Wang A.
      • Gao J.L.
      • Murphy P.M.
      • Wang J.M.
      Formylpeptide receptors are critical for rapid neutrophil mobilization in host defense against Listeria monocytogenes.
      • Gao J.L.
      • Lee E.J.
      • Murphy P.M.
      Impaired antibacterial host defense in mice lacking the N-formylpeptide receptor.
      Furthermore, Streptococcus pneumoniae meningeal infection is associated with poorer outcome in Fpr1−/− animals but, interestingly, a paradoxical increase in neutrophil number within the brain.
      • Oldekamp S.
      • Pscheidl S.
      • Kress E.
      • Soehnlein O.
      • Jansen S.
      • Pufe T.
      • Wang J.M.
      • Tauber S.C.
      • Brandenburg L.O.
      Lack of formyl peptide receptor 1 and 2 leads to more severe inflammation and higher mortality in mice with of pneumococcal meningitis.
      Consistent with FPR1 having a central role in pathogen containment, S. aureus secretes an FPR1 inhibitory protein as a potential immune-evasion strategy.
      • Prat C.
      • Haas P.J.
      • Bestebroer J.
      • de Haas C.J.
      • van Strijp J.A.
      • van Kessel K.P.
      A homolog of formyl peptide receptor-like 1 (FPRL1) inhibitor from Staphylococcus aureus (FPRL1 inhibitory protein) that inhibits FPRL1 and FPR.
      In contrast, within the lung, susceptibility to pulmonary S. pneumoniae infection is not increased in Fpr1−/− mice or in wild-type animals treated with pharmacological inhibitors of FPR1, such as cyclosporin H.
      • Fillion I.
      • Ouellet N.
      • Simard M.
      • Bergeron Y.
      • Sato S.
      • Bergeron M.G.
      Role of chemokines and formyl peptides in pneumococcal pneumonia-induced monocyte/macrophage recruitment.
      • Gauthier J.F.
      • Fortin A.
      • Bergeron Y.
      • Dumas M.C.
      • Champagne M.E.
      • Bergeron M.G.
      Differential contribution of bacterial N-formyl-methionyl-leucyl- phenylalanine and host-derived CXC chemokines to neutrophil infiltration into pulmonary alveoli during murine pneumococcal pneumonia.
      Indeed, a reduction in neutrophil number after pharmacological FPR1 inhibition has instead been demonstrated to have no effect on bacterial burden.
      • Gauthier J.F.
      • Fortin A.
      • Bergeron Y.
      • Dumas M.C.
      • Champagne M.E.
      • Bergeron M.G.
      Differential contribution of bacterial N-formyl-methionyl-leucyl- phenylalanine and host-derived CXC chemokines to neutrophil infiltration into pulmonary alveoli during murine pneumococcal pneumonia.
      In a model of bacterial endotoxin-mediated lung injury, Fpr1−/− mice had a reduction in alveolar, interstitial, and circulating neutrophil numbers, as well as extravascular leak, 4 hours after injury with nebulized LPS.
      • Grommes J.
      • Drechsler M.
      • Soehnlein O.
      CCR5 and FPR1 mediate neutrophil recruitment in endotoxin-induced lung injury.
      Whether these seemingly paradoxical observations are due to organ, pathogen, or model-specific differences remains to be seen.
      Cigarette smoke contains a wide variety of bacterial products, including LPS and formylated peptides.
      • Hasday J.D.
      • Bascom R.
      • Costa J.J.
      • Fitzgerald T.
      • Dubin W.
      Bacterial endotoxin is an active component of cigarette smoke.
      Demonstrating the importance of FPR1 in both the initiation and propagation of pulmonary inflammation, Cardini et al
      • Cardini S.
      • Dalli J.
      • Fineschi S.
      • Perretti M.
      • Lungarella G.
      • Lucattelli M.
      Genetic ablation of the fpr1 gene confers protection from smoking-induced lung emphysema in mice.
      found that wild-type mice chronically exposed to cigarette smoke over a 7-month period developed characteristic emphysematous changes. In contrast, Fpr1−/− animals were protected from emphysema, suggesting that the formylated peptides within cigarette smoke are central to disease pathogenesis. A similarly beneficial reduction in inflammatory response, with fewer migrating neutrophils and macrophages and lower proinflammatory cytokine levels, was observed after acute or subacute exposure (1 to 3 days) to cigarette smoke.
      • Cardini S.
      • Dalli J.
      • Fineschi S.
      • Perretti M.
      • Lungarella G.
      • Lucattelli M.
      Genetic ablation of the fpr1 gene confers protection from smoking-induced lung emphysema in mice.
      Whether the chronic changes observed are attributable to an alteration in initial inflammatory cell phenotype or are a result of a modulation of the chronic inflammatory response through both innate and adaptive immune response remains to be elucidated.
      Further novel perspectives on the role of FPR1 in infection have come through the description of the essential role of neutrophil-derived IL-1β in abscess formation and bacterial clearance after cutaneous S. aureus infection.
      • Cho J.S.
      • Guo Y.
      • Ramos R.I.
      • Hebroni F.
      • Plaisier S.B.
      • Xuan C.
      • Granick J.L.
      • Matsushima H.
      • Takashima A.
      • Iwakura Y.
      • Cheung A.L.
      • Cheng G.
      • Lee D.J.
      • Simon S.I.
      • Miller L.S.
      Neutrophil-derived IL-1beta is sufficient for abscess formation in immunity against Staphylococcus aureus in mice.
      Alongside animals deficient in Toll-like receptor (Tlr) 2 and nucleotide-binding oligomerization domain (Nod) 2, Fpr1−/− mice were noted to have a reduced neutrophil number at the site of infection, with an associated reduction in IL-1β release after direct bacterial infection in vitro, suggesting another mechanism through which this GPCR exerts its antibacterial functions.
      • Cho J.S.
      • Guo Y.
      • Ramos R.I.
      • Hebroni F.
      • Plaisier S.B.
      • Xuan C.
      • Granick J.L.
      • Matsushima H.
      • Takashima A.
      • Iwakura Y.
      • Cheung A.L.
      • Cheng G.
      • Lee D.J.
      • Simon S.I.
      • Miller L.S.
      Neutrophil-derived IL-1beta is sufficient for abscess formation in immunity against Staphylococcus aureus in mice.

      FPR1 in Other Cell Types

      The most frequently described roles for FPR1 are with regard to neutrophil chemotaxis, degranulation, and ROS production, but FPR1 activation also exerts effects in other cell types. In isolated human monocytes, FPR1 activation augments IL-8 release in a manner cooperative with other mitochondrial damage-associated molecular patterns
      • Crouser E.D.
      • Shao G.
      • Julian M.W.
      • Macre J.E.
      • Shadel G.S.
      • Tridandapani S.
      • Huang Q.
      • Wewers M.D.
      Monocyte activation by necrotic cells is promoted by mitochondrial proteins and formyl peptide receptors.
      while also influencing dendritic cell maturation, migration, and phenotype.
      • Kang H.K.
      • Lee H.Y.
      • Kim M.K.
      • Park K.S.
      • Park Y.M.
      • Kwak J.Y.
      • Bae Y.S.
      The synthetic peptide Trp-Lys-Tyr-Met-Val-D-Met inhibits human monocyte-derived dendritic cell maturation via formyl peptide receptor and formyl peptide receptor-like 2.
      • Tae Y.M.
      • Park H.T.
      • Moon H.G.
      • Kim Y.S.
      • Jeon S.G.
      • Roh T.Y.
      • Bae Y.S.
      • Gho Y.S.
      • Ryu S.H.
      • Kwon H.S.
      • Kim Y.K.
      Airway activation of formyl peptide receptors inhibits Th1 and Th17 cell responses via inhibition of mediator release from immune and inflammatory cells and maturation of dendritic cells.
      Importantly, the number of FPR1 receptors on the macrophage surface appears linked to their phenotype, at least in vitro, as treatment with cytokines associated with inducing an alternatively activated phenotype (IL-4 and IL-13) reduced FPR1 through Stat6-dependent mechanisms, whereas interferon γ (associated with a classically activated phenotype) increased receptor expression.
      • Gemperle C.
      • Schmid M.
      • Herova M.
      • Marti-Jaun J.
      • Wuest S.J.
      • Loretz C.
      • Hersberger M.
      Regulation of the formyl peptide receptor 1 (FPR1) gene in primary human macrophages.
      • Dai Y.
      • Major J.
      • Novotny M.
      • Hamilton T.A.
      IL-4 inhibits expression of the formyl peptide receptor gene in mouse peritoneal macrophages.
      Importantly, in the former group, fMLF-induced migration was completely abrogated, suggesting regulation of cell migration into the inflammatory environment by autocrine and paracrine manipulation of GPCR expression.
      In addition to the direct regulation of immune cells, the role of bacteria-derived formylated peptides in mediating nociceptive responses to infection has recently been delineated. S. aureus skin infection causes hyperalgesic responses that were found to be independent of infiltrating immune cells but instead dependent on formylated peptides and the bacterial pore-forming toxin α-hemolysin, with protection in Fpr1−/− mice noted.
      • Chiu I.M.
      • Heesters B.A.
      • Ghasemlou N.
      • Von Hehn C.A.
      • Zhao F.
      • Tran J.
      • Wainger B.
      • Strominger A.
      • Muralidharan S.
      • Horswill A.R.
      • Bubeck Wardenburg J.
      • Hwang S.W.
      • Carroll M.C.
      • Woolf C.J.
      Bacteria activate sensory neurons that modulate pain and inflammation.
      Interestingly, inhibition of nociceptor responses led to enhanced local inflammation, demonstrating that formylated peptides can have indirect immune-modulatory properties acting via neuronal cell types.
      • Chiu I.M.
      • Heesters B.A.
      • Ghasemlou N.
      • Von Hehn C.A.
      • Zhao F.
      • Tran J.
      • Wainger B.
      • Strominger A.
      • Muralidharan S.
      • Horswill A.R.
      • Bubeck Wardenburg J.
      • Hwang S.W.
      • Carroll M.C.
      • Woolf C.J.
      Bacteria activate sensory neurons that modulate pain and inflammation.
      Recent evidence has also emerged of a protective role for FPR1 in the maintenance of epithelial integrity and mucosal repair after colonic injury in vivo. Indeed, formylated peptides released by commensal bacteria within the colon promote enterocyte migration and proliferation through FPR1 and NADPH oxidase 1.
      • Alam A.
      • Leoni G.
      • Wentworth C.C.
      • Kwal J.M.
      • Wu H.
      • Ardita C.S.
      • Swanson P.A.
      • Lambeth J.D.
      • Jones R.M.
      • Nusrat A.
      • Neish A.S.
      Redox signaling regulates commensal-mediated mucosal homeostasis and restitution and requires formyl peptide receptor 1.
      Furthermore, binding of AnnA1 and Ac2-26, its N-terminal derivative, to epithelial FPR1 results in Src kinase and NADPH oxidase 1 activation and increased ROS production. Subsequent oxidative inactivation of regulatory phosphatases, phosphatase and tensin homologue, and protein tyrosine phosphatase containing proline, glutamic acid, serine, and threonine residues (PTP-PEST) leads to paxillin and focal adhesion kinase–mediated epithelial migration and wound closure.
      • Leoni G.
      • Alam A.
      • Neumann P.A.
      • Lambeth J.D.
      • Cheng G.
      • McCoy J.
      • Hilgarth R.S.
      • Kundu K.
      • Murthy N.
      • Kusters D.
      • Reutelingsperger C.
      • Perretti M.
      • Parkos C.A.
      • Neish A.S.
      • Nusrat A.
      Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.
      In vivo, delivery of exogenous AnnA1 resulted in accelerated recovery after chemical-induced colitis.
      • Leoni G.
      • Alam A.
      • Neumann P.A.
      • Lambeth J.D.
      • Cheng G.
      • McCoy J.
      • Hilgarth R.S.
      • Kundu K.
      • Murthy N.
      • Kusters D.
      • Reutelingsperger C.
      • Perretti M.
      • Parkos C.A.
      • Neish A.S.
      • Nusrat A.
      Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.
      Despite this latter observation, a similarly important role for FPR1 has been seen in vitro in human bronchial epithelial cell migration, with an FPR1-dependent response to mitochondrial formylated peptides observed after linear scratch injury to cells in culture.
      • Shao G.
      • Julian M.W.
      • Bao S.
      • McCullers M.K.
      • Lai J.P.
      • Knoell D.L.
      • Crouser E.D.
      Formyl peptide receptor ligands promote wound closure in lung epithelial cells.
      The in vivo corollary and functional relevance of FPR1-mediated pulmonary epithelial homeostasis is, however, yet to be established.
      • Shao G.
      • Julian M.W.
      • Bao S.
      • McCullers M.K.
      • Lai J.P.
      • Knoell D.L.
      • Crouser E.D.
      Formyl peptide receptor ligands promote wound closure in lung epithelial cells.
      Additional evidence for the importance of Fpr1 in epithelial homeostasis lies in the observation that Fpr1−/− mice develop spontaneous lens degeneration in the absence of any preceding inflammatory events,
      • Schneider E.H.
      • Weaver J.D.
      • Gaur S.S.
      • Tripathi B.K.
      • Jesaitis A.J.
      • Zelenka P.S.
      • Gao J.L.
      • Murphy P.M.
      The leukocyte chemotactic receptor FPR1 is functionally expressed on human lens epithelial cells.
      whereas the presence of formylated peptides accelerates human retinal pigment epithelial cell migration after injury.
      • Zhang X.G.
      • Hui Y.N.
      • Huang X.F.
      • Du H.J.
      • Zhou J.
      • Ma J.X.
      Activation of formyl peptide receptor-1 enhances restitution of human retinal pigment epithelial cell monolayer under electric fields.
      Conversely, up-regulation of expression in malignant cells may confer a more aggressive and invasive phenotype due to an increased propensity of cells to migrate.
      • Huang J.
      • Chen K.
      • Chen J.
      • Gong W.
      • Dunlop N.M.
      • Howard O.M.
      • Gao Y.
      • Bian X.W.
      • Wang J.M.
      The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells.
      In keratinocytes, FPR1 has been shown, within specific clinical contexts, to play an important role in the control of necroptosis (caspase-independent programed cell death). In patients with severe blistering skin conditions, such as Stevens-Johnson syndrome, keratinocytes, when cultured in vitro, were sensitive to the FPR1 agonists fMLF and AnnA1, resulting in necroptosis through ROS production and receptor-interacting protein.
      • Saito N.
      • Qiao H.
      • Yanagi T.
      • Shinkuma S.
      • Nishimura K.
      • Suto A.
      • Fujita Y.
      • Suzuki S.
      • Nomura T.
      • Nakamura H.
      • Nagao K.
      • Obuse C.
      • Shimizu H.
      • Abe R.
      An annexin A1–FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions.
      The limited nature of this observation is attributed to differences in inducible expression of FPR1, which is greater in Stevens-Johnson syndrome than in other similar dermatological conditions despite no differences in promoter sequence.
      • Saito N.
      • Qiao H.
      • Yanagi T.
      • Shinkuma S.
      • Nishimura K.
      • Suto A.
      • Fujita Y.
      • Suzuki S.
      • Nomura T.
      • Nakamura H.
      • Nagao K.
      • Obuse C.
      • Shimizu H.
      • Abe R.
      An annexin A1–FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions.
      This role in keratinocyte death is in contrast to the proposed beneficial effects of FPR1,
      • Leoni G.
      • Alam A.
      • Neumann P.A.
      • Lambeth J.D.
      • Cheng G.
      • McCoy J.
      • Hilgarth R.S.
      • Kundu K.
      • Murthy N.
      • Kusters D.
      • Reutelingsperger C.
      • Perretti M.
      • Parkos C.A.
      • Neish A.S.
      • Nusrat A.
      Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair.
      in particular on binding AnnA1, in the maintenance of gastrointestinal epithelial integrity and warrants further investigation.

      Inhibition of FPR1

      Accompanying the increased understanding of the pathophysiological role of FPR1 is the appreciation of its potential as a therapeutic target in chronic inflammatory disorders or acute sterile inflammation either through the use of agonists or antagonists, depending on the context. With regard to pharmacological antagonists, there are, at present, limited FPR1-specific compounds available. Initially, Boc-Met-Leu-Phe-OH (Boc-MLF; alias Boc-1) and subsequent Boc-Phe-Leu-Phe-Leu-Phe-OH (Boc-FLFLF; alias Boc-2) were described,
      • Stenfeldt A.L.
      • Karlsson J.
      • Wennerås C.
      • Bylund J.
      • Fu H.
      • Dahlgren C.
      Cyclosporin H, Boc-MLF and Boc-FLFLF are antagonists that preferentially inhibit activity triggered through the formyl peptide receptor.
      but their relative low potency and lack of specificity given associated FPR2 inhibition have led to cyclosporin H, an inverse agonist to FPR1, being the more readily used agent in preclinical studies.
      • Hauser C.J.
      • Sursal T.
      • Rodriguez E.K.
      • Appleton P.T.
      • Zhang Q.
      • Itagaki K.
      Mitochondrial damage associated molecular patterns from femoral reamings activate neutrophils through formyl peptide receptors and P44/42 MAP kinase.
      • McDonald B.
      • Pittman K.
      • Menezes G.B.
      • Hirota S.A.
      • Slaba I.
      • Waterhouse C.C.
      • Beck P.L.
      • Muruve D.A.
      • Kubes P.
      Intravascular danger signals guide neutrophils to sites of sterile inflammation.
      • Gauthier J.F.
      • Fortin A.
      • Bergeron Y.
      • Dumas M.C.
      • Champagne M.E.
      • Bergeron M.G.
      Differential contribution of bacterial N-formyl-methionyl-leucyl- phenylalanine and host-derived CXC chemokines to neutrophil infiltration into pulmonary alveoli during murine pneumococcal pneumonia.
      • Cardini S.
      • Dalli J.
      • Fineschi S.
      • Perretti M.
      • Lungarella G.
      • Lucattelli M.
      Genetic ablation of the fpr1 gene confers protection from smoking-induced lung emphysema in mice.
      Its specificity is limited by the off-target effects on calcium/calmodulin–dependent phosphorylation of elongation factor 2.
      • Schepetkin I.A.
      • Khlebnikov A.I.
      • Giovannoni M.P.
      • Kirpotina L.N.
      • Cilibrizzi A.
      • Quinn M.T.
      Development of small molecule non-peptide formyl peptide receptor (FPR) ligands and molecular modeling of their recognition.
      Studies that are based on observations made entirely using these compounds should therefore be interpreted with caution and need to be accompanied by adjunctive demonstrations of FPR1 inhibition with monoclonal antibodies or, in the murine context, the use of Fpr1 knockout animals.
      Emphasis has therefore shifted to the development of alternative synthetic peptide ligands and small molecules, agonists and antagonists that were recently reviewed elsewhere.
      • Schepetkin I.A.
      • Khlebnikov A.I.
      • Giovannoni M.P.
      • Kirpotina L.N.
      • Cilibrizzi A.
      • Quinn M.T.
      Development of small molecule non-peptide formyl peptide receptor (FPR) ligands and molecular modeling of their recognition.
      Several synthetic ligands inhibiting fMLF-induced neutrophil chemotaxis have been described
      • Brullo C.
      • Spisani S.
      • Selvatici R.
      • Bruno O.
      N-Aryl-2-phenyl-2,3-dihydro-imidazo[1,2-b]pyrazole-1-carboxamides 7-substituted strongly inhibiting both fMLP-OMe- and IL-8-induced human neutrophil chemotaxis.
      • Selvatici R.
      • Brullo C.
      • Bruno O.
      • Spisani S.
      Differential inhibition of signaling pathways by two new imidazo-pyrazoles molecules in fMLF-OMe- and IL8-stimulated human neutrophil.
      ; however, their inhibitory effects may be through the inhibition of downstream signaling pathways rather than direct FPR1 antagonism. Given difficulties in the synthesis and delivery of peptides, a complementary focus has been on the development of small-molecule antagonists and the use of high-throughput screening and structure–activity relationship–directed design and synthesis.
      • Unitt J.
      • Fagura M.
      • Phillips T.
      • King S.
      • Perry M.
      • Morley A.
      • MacDonald C.
      • Weaver R.
      • Christie J.
      • Barber S.
      • Mohammed R.
      • Paul M.
      • Cook A.
      • Baxter A.
      Discovery of small molecule human FPR1 receptor antagonists.
      • Pinilla C.
      • Edwards B.S.
      • Appel J.R.
      • Yates-Gibbins T.
      • Giulianotti M.A.
      • Medina-Franco J.L.
      • Young S.M.
      • Santos R.G.
      • Sklar L.A.
      • Houghten R.A.
      Selective agonists and antagonists of formylpeptide receptors: duplex flow cytometry and mixture-based positional scanning libraries.
      Notably, this approach has recently identified particular chromones and isoflavones that are selective for FPR1 and do not alter FPR2-mediated ERK phosphorylation and intracellular calcium flux.
      • Kirpotina L.N.
      • Khlebnikov A.I.
      • Schepetkin I.A.
      • Ye R.D.
      • Rabiet M.J.
      • Jutila M.A.
      • Quinn M.T.
      Identification of novel small-molecule agonists for human formyl peptide receptors and pharmacophore models of their recognition.

      Conclusion

      FPR1, as a stereotypical GPCR, has facilitated significant advances in our understanding of receptor signaling and control of multiple cell functions at a single-cell level. It has, however, been the identification of surrogate biomarkers of the release of mitochondrial products (elevated plasma mtDNA in trauma, sepsis, and systemic inflammatory response syndrome), the development and application of transgenic mouse models into a variety of disease models, and the awareness of FPR1 functions in nonmyeloid cells that has now firmly established the functional importance of FPR1 in the pathophysiology of a plethora of inflammatory diseases. Whether FPR1 antagonism, which interferes with the bactericidal capacity of neutrophils, risks precipitating or exacerbating intercurrent infection remains to be shown in appropriate animal models. However, in the context of the many neutrophil-dominant sterile inflammatory disease processes that affect humans, FPR1 antagonism may prove beneficial. Therefore, the development of small-molecule antagonists and the appreciation of its ligand-dependent and potential proresolution effects have placed FPR1 in the arena of attractive novel therapeutic targets.

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