The Role of Formyl Peptide Receptors in Permanent and Low-Grade Inflammation: Helicobacter pylori Infection as a Model

Formyl peptide receptors (FPRs) are cell surface pattern recognition receptors (PRRs), belonging to the chemoattractant G protein-coupled receptors (GPCRs) family. They play a key role in the innate immune system, regulating both the initiation and the resolution of the inflammatory response. FPRs were originally identified as receptors with high binding affinity for bacteria or mitochondria N-formylated peptides. However, they can also bind a variety of structurally different ligands. Among FPRs, formyl peptide receptor-like 1 (FPRL1) is the most versatile, recognizing N-formyl peptides, non-formylated peptides, and synthetic molecules. In addition, according to the ligand nature, FPRL1 can mediate either pro- or anti-inflammatory responses. Hp(2-20), a Helicobacter pylori-derived, non-formylated peptide, is a potent FPRL1 agonist, participating in Helicobacter pylori-induced gastric inflammation, thus contributing to the related site or not-site specific diseases. The aim of this review is to provide insights into the role of FPRs in H. pylori-associated chronic inflammation, which suggests this receptor as potential target to mitigate both microbial and sterile inflammatory diseases.

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A long-lived peptide-conjugated iridium(iii) complex as a luminescent probe and inhibitor of the cell migration mediator, formyl peptide receptor 2

Chemical Science ◽

10.1039/c8sc02733a ◽

2018 ◽

Vol 9 (43) ◽

pp. 8171-8177 ◽

Cited By ~ 36

Author(s):

Kasipandi Vellaisamy ◽

Guodong Li ◽

Wanhe Wang ◽

Chung-Hang Leung ◽

Dik-Lung Ma

Keyword(s):

Cell Migration ◽

Wound Repair ◽

Inflammatory Diseases ◽

Formyl Peptide Receptor ◽

Luminescent Probe ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Peptide Receptor ◽

Formyl Peptide

Formyl peptide receptors play important biological and therapeutic roles in wound repair and inflammatory diseases.

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The Role of Formyl Peptide Receptors in Neurological Diseases via Regulating Inflammation

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.753832 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jiahui Zhu ◽

Lingfei Li ◽

Jiao Ding ◽

Jinyu Huang ◽

Anwen Shao ◽

...

Keyword(s):

Inflammatory Responses ◽

Neurological Diseases ◽

Cell Types ◽

Dual Function ◽

Peptide Receptors ◽

Regulatory Pathways ◽

Formyl Peptide Receptors ◽

Neurogenic Tumors ◽

Formyl Peptide

Formyl peptide receptors (FPRs) are a group of G protein-coupled cell surface receptors that play important roles in host defense and inflammation. Owing to the ubiquitous expression of FPRs throughout different cell types and since they interact with structurally diverse chemotactic agonists, they have a dual function in inflammatory processes, depending on binding with different ligands so that accelerate or inhibit key intracellular kinase-based regulatory pathways. Neuroinflammation is closely associated with the pathogenesis of neurodegenerative diseases, neurogenic tumors and cerebrovascular diseases. From recent studies, it is clear that FPRs are important biomarkers for neurological diseases as they regulate inflammatory responses by monitoring glial activation, accelerating neural differentiation, regulating angiogenesis, and controlling blood brain barrier (BBB) permeability, thereby affecting neurological disease progression. Given the complex mechanisms of neurological diseases and the difficulty of healing, we are eager to find new and effective therapeutic targets. Here, we review recent research about various mechanisms of the effects generated after FPR binding to different ligands, role of FPRs in neuroinflammation as well as the development and prognosis of neurological diseases. We summarize that the FPR family has dual inflammatory functional properties in central nervous system. Emphasizing that FPR2 acts as a key molecule that mediates the active resolution of inflammation, which binds with corresponding receptors to reduce the expression and activation of pro-inflammatory composition, govern the transport of immune cells to inflammatory tissues, and restore the integrity of the BBB. Concurrently, FPR1 is essentially related to angiogenesis, cell proliferation and neurogenesis. Thus, treatment with FPRs-modulation may be effective for neurological diseases.

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The Role of Formyl Peptide Receptors in Microbial Infection and Inflammation

Current Medicinal Chemistry - Anti-Infective Agents ◽

10.2174/1568012033354630 ◽

2003 ◽

Vol 2 (1) ◽

pp. 83-93 ◽

Cited By ~ 2

Author(s):

Yingying Le ◽

Ronghua Sun ◽

Guoguang Ying ◽

Pablo Iribarren ◽

Ji Wang

Keyword(s):

Microbial Infection ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Formyl Peptide ◽

Infection And Inflammation

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Multiple domains of the N-formyl peptide receptor are required for high-affinity ligand binding. Construction and analysis of chimeric N-formyl peptide receptors.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)46825-6 ◽

1993 ◽

Vol 268 (24) ◽

pp. 18167-18175 ◽

Cited By ~ 3

Author(s):

O. Quehenberger ◽

E.R. Prossnitz ◽

S.L. Cavanagh ◽

C.G. Cochrane ◽

R.D. Ye

Keyword(s):

Ligand Binding ◽

Formyl Peptide Receptor ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Peptide Receptor ◽

High Affinity ◽

Affinity Ligand ◽

Formyl Peptide ◽

Multiple Domains ◽

High Affinity Ligand

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Formyl-Peptide Receptor Activation Enhances Phagocytosis of Community-Acquired Methicillin-Resistant Staphylococcus aureus

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz498 ◽

2019 ◽

Cited By ~ 1

Author(s):

Elisabeth Weiß ◽

Katja Schlatterer ◽

Christian Beck ◽

Andreas Peschel ◽

Dorothee Kretschmer

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Receptor Activation ◽

Formyl Peptide Receptor ◽

Peptide Receptors ◽

Highly Pathogenic ◽

Methicillin Resistant ◽

Formyl Peptide Receptors ◽

Formyl Peptide ◽

First Time

Abstract Background Formyl-peptide receptors (FPRs) are important pattern recognition receptors that sense specific bacterial peptides. Formyl-peptide receptors are highly expressed on neutrophils and monocytes, and their activation promotes the migration of phagocytes to sites of infection. It is currently unknown whether FPRs may also influence subsequent processes such as bacterial phagocytosis and killing. Staphylococcus aureus, especially highly pathogenic community-acquired methicillin-resistant S aureus strains, release high amounts of FPR2 ligands, the phenol-soluble modulins. Methods We demonstrate that FPR activation leads to upregulation of complement receptors 1 and 3 as well as FCγ receptor I on neutrophils and, consequently, increased opsonic phagocytosis of S aureus and other pathogens. Results Increased phagocytosis promotes killing of S aureus and interleukin-8 release by neutrophils. Conclusions We show here for the first time that FPRs govern opsonic phagocytosis. Manipulation of FPR2 activation could open new therapeutic opportunities against bacterial pathogens.

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The Role of Formyl Peptide Receptors for Immunomodulatory Activities of Antimicrobial Peptides and Peptidomimetics

Current Pharmaceutical Design ◽

10.2174/1381612824666180403123233 ◽

2018 ◽

Vol 24 (10) ◽

pp. 1100-1120 ◽

Cited By ~ 13

Author(s):

Sarah Line Skovbakke ◽

Andre Holdfeldt ◽

Huamei Forsman ◽

Johan Bylund ◽

Henrik Franzyk

Keyword(s):

Antimicrobial Peptides ◽

Therapeutic Potential ◽

Biological Activities ◽

Chemical Properties ◽

Immunomodulatory Activity ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Formyl Peptide ◽

Natural And Synthetic

In recent years, the therapeutic potential of antimicrobial peptides (AMPs) as immunomodulators has become generally accepted. Nevertheless, only very few AMP-based compounds have progressed into clinical trials. This paradox may be explained by the fact, that some of the intrinsic properties of natural peptides, such as proteolytic and oxidative instability, render them inconvenient as therapeutics. Therefore, substantial research efforts have been dedicated to mimic the physico-chemical properties as well as biological activities of AMPs by designing and identifying more stable peptidomimetics displaying analogous immunomodulatory activity profiles. Neutrophils play key roles in host defense as major effector cells in clearance of pathogens by phagocytosis and by regulating other processes of innate immunity as well as by promoting resolution of inflammation. Several aspects of these effects are correlated to their expression of formyl peptide receptors (FPRs) that have been shown to be targets of both natural and synthetic antimicrobial peptides. In the present review recent findings highlighting the role of FPRs in mediating immunomodulatory activities of natural and synthetic AMPs as well as of stabilized peptidomimetics are discussed, and prospects for future development of immunomodulatory therapeutics are presented.

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N-Formyl Peptide Receptors Display an Asymmetric Distribution In Migrating Human Neutrophils

Microscopy and Microanalysis ◽

10.1017/s143192760001895x ◽

1999 ◽

Vol 5 (S2) ◽

pp. 1126-1127

Author(s):

Vesa-Matti Loitto ◽

Birgitta Rasmusson ◽

Karl-Eric Magnusson

Keyword(s):

Cell Movement ◽

Ccd Camera ◽

Formyl Peptide Receptor ◽

Human Neutrophils ◽

Asymmetric Distribution ◽

Phagocytic Cells ◽

Peptide Receptors ◽

Directed Movement ◽

Formyl Peptide Receptors ◽

Formyl Peptide

A debated and yet unanswered question, in regard to polarization and directed movement of phagocytic cells, concerns the distribution of chemoattractant receptors during cell locomotion1. We have therefore studied the instantaneous distribution of N-formyl-peptide receptors on living neutrophils. Using a fluorescent N-formyl-peptide receptor antagonist, tert-butyloxycarbonyl-Phe(D)-Leu-Phe(D)-Leu-Phe-OH (Boc-FLFLF), and a fluorescent receptor agonist, formyl-Nle-Leu-Phe-Nle-Tyr-Lys (fnLLFnLYK), the localization of the chemoattractant receptors could be followed during random migratio2. Neutrophils were adhered to plasma-coated coverslips. A Nomarski differential interference contrast (DIC)- image was taken, and rapidly followed by a fluorescence-image captured with a water-cooled, slow-scan CCD-camera. Then a second DIC-image was directly recorded to reveal the direction of cell movement.Using fnLLFnLYK we observed that the distribution of N-formyl-peptide receptors was clearly heterogeneous as shown in figure. Fluorescence was concentrated mainly at the rear and front of elongated locomoting cells, leaving the cell body almost non-fluorescent.

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Annexin A1 Released in Extracellular Vesicles by Pancreatic Cancer Cells Activates Components of the Tumor Microenvironment, through Interaction with the Formyl-Peptide Receptors

Cells ◽

10.3390/cells9122719 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2719

Author(s):

Nunzia Novizio ◽

Raffaella Belvedere ◽

Emanuela Pessolano ◽

Alessandra Tosco ◽

Amalia Porta ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Extracellular Vesicles ◽

Soluble Form ◽

Annexin A1 ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Pancreatic Cancer Cells ◽

Formyl Peptide

Pancreatic cancer (PC) is one of the most aggressive cancers in the world. Several extracellular factors are involved in its development and metastasis to distant organs. In PC, the protein Annexin A1 (ANXA1) appears to be overexpressed and may be identified as an oncogenic factor, also because it is a component in tumor-deriving extracellular vesicles (EVs). Indeed, these microvesicles are known to nourish the tumor microenvironment. Once we evaluated the autocrine role of ANXA1-containing EVs on PC MIA PaCa-2 cells and their pro-angiogenic action, we investigated the ANXA1 paracrine effect on stromal cells like fibroblasts and endothelial ones. Concerning the analysis of fibroblasts, cell migration/invasion, cytoskeleton remodeling, and the different expression of specific protein markers, all features of the cell switching into myofibroblasts, were assessed after administration of wild type more than ANXA1 Knock-Out EVs. Interestingly, we demonstrated a mechanism by which the ANXA1-EVs complex can stimulate the activation of formyl peptide receptors (FPRs), triggering mesenchymal switches and cell motility on both fibroblasts and endothelial cells. Therefore, we highlighted the importance of ANXA1/EVs-FPR axes in PC progression as a vehicle of intercommunication tumor cells-stroma, suggesting a specific potential prognostic/diagnostic role of ANXA1, whether in soluble form or even if EVs are captured in PC.

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