Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression

G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases.

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The two formyl peptide receptors differently regulate GPR84-mediated neutrophil NADPH-oxidase activity

10.1101/2020.11.13.381582 ◽

2020 ◽

Author(s):

Jonas Mårtensson ◽

Martina Sundqvist ◽

Asmita Manandhar ◽

Loukas Ieremias ◽

Linjie Zhang ◽

...

Keyword(s):

Nadph Oxidase ◽

Oxidase Activity ◽

Human Neutrophils ◽

Ros Generation ◽

Ros Production ◽

Peptide Receptors ◽

Nadph Oxidase Activity ◽

Formyl Peptide Receptors ◽

Formyl Peptide ◽

Specific Antagonist

ABSTRACTNeutrophils express many G protein-coupled receptors (GPCRs) including the two formyl peptide receptors (FPR1 and FPR2) and the medium chain fatty acid receptor GPR84. The FPRs are known to define a hierarchy among neutrophil GPCRs, i.e., the GPCR-mediated response can be either suppressed or amplified by signals generated by FPRs. In this study, we investigated the position of GPR84 in the FPR-defined hierarchy regarding the activation of neutrophil NADPH-oxidase, an enzyme system designed to generate reactive oxygen species (ROS). When naïve neutrophils are activated by GPR84 agonists a modest ROS release was induced. However, vast amounts of ROS production was induced by these GPR84 agonists in FPR2-desensitized neutrophils, and the response is inhibited not only by a GPR84 antagonist but also by an FPR2 specific antagonist. This suggests that the amplified GPR84 agonist response is achieved through a reactivation of the desensitized FPR2. In addition, the GPR84-mediated FPR2 reactivation was independent of β-arrestin recruitment and sensitive to a protein phosphatase inhibitor. In contrast, the modest ROS production induced by GPR84 agonists was primarily suppressed in FPR1-desensitized neutrophils through hierarchical desensitization of GPR84 by FPR1 generated signals.In summary, our data show that FPRs control the NADPH-oxidase activity mediated through GPR84 in human neutrophils. While an amplified ROS generation is achieved by GPR84 agonists through reactivation of desensitized FPR2, FPR1 heterologously desensitizes GPR84 and by that suppresses the release of ROS induced by GPR84 agonists.

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Intracellular Signaling Triggered by Formyl-Peptide Receptors in Nonphagocytic Cells

Current Signal Transduction Therapy ◽

10.2174/157436208784223152 ◽

2008 ◽

Vol 3 (2) ◽

pp. 88-96 ◽

Cited By ~ 6

Author(s):

Annalisa Iaccio ◽

Antonella Angiolillo ◽

Rosario Ammendola

Keyword(s):

Intracellular Signaling ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Formyl Peptide

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Reactivation of Formyl Peptide Receptors Triggers the Neutrophil NADPH-oxidase but Not a Transient Rise in Intracellular Calcium

Journal of Biological Chemistry ◽

10.1074/jbc.m209202200 ◽

2003 ◽

Vol 278 (33) ◽

pp. 30578-30586 ◽

Cited By ~ 37

Author(s):

Johan Bylund ◽

Åse Björstad ◽

Daniel Granfeldt ◽

Anna Karlsson ◽

Charlotte Woschnagg ◽

...

Keyword(s):

Nadph Oxidase ◽

Intracellular Calcium ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Transient Rise ◽

Formyl Peptide

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Crotoxin is responsible for the long-lasting anti-inflammatory effect of Crotalus durissus terrificus snake venom: involvement of formyl peptide receptors

Toxicon ◽

10.1016/j.toxicon.2009.12.011 ◽

2010 ◽

Vol 55 (6) ◽

pp. 1100-1106 ◽

Cited By ~ 24

Author(s):

F.P.B. Nunes ◽

B.C. Zychar ◽

M.S. Della-Casa ◽

S.C. Sampaio ◽

L.R.C. Gonçalves ◽

...

Keyword(s):

Snake Venom ◽

Peptide Receptors ◽

Crotalus Durissus Terrificus ◽

Formyl Peptide Receptors ◽

Formyl Peptide ◽

Anti Inflammatory ◽

Crotalus Durissus ◽

Inflammatory Effect

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The sensing of bacteria: emerging principles for the detection of signal sequences by formyl peptide receptors

BioMolecular Concepts ◽

10.1515/bmc-2016-0013 ◽

2016 ◽

Vol 7 (3) ◽

pp. 205-214 ◽

Cited By ~ 12

Author(s):

Bernd Bufe ◽

Frank Zufall

Keyword(s):

Molecular Mechanisms ◽

Immune Defense ◽

The Body ◽

Signal Peptides ◽

Peptide Receptors ◽

Signal Sequences ◽

Specific Chemical ◽

Formyl Peptide Receptors ◽

Specificity And Sensitivity ◽

Formyl Peptide

AbstractThe ability to detect specific chemical signatures released by bacteria and other microorganisms is a fundamental feature of immune defense against pathogens. There is increasing evidence that chemodetection of such microorganism-associated molecular patterns (MAMPs) occurs at many places in the body including specific sets of chemosensory neurons in the mammalian nose. Formyl peptide receptors (FPRs) are a unique family of G protein-coupled receptors (GPCRs) that can detect the presence of bacteria and function as chemotactic receptors. Here, we highlight the recent discovery of a vast family of natural FPR agonists, the bacterial signal peptides (or signal sequences), thus providing new insight into the molecular mechanisms of bacterial sensing by human and mouse FPRs. Signal peptides in bacteria are formylated, N-terminal protein signatures required for directing the transfer of proteins through the plasma membrane. After their cleavage and release, signal peptides are available for FPR detection and thus provide a previously unrecognized MAMP. With over 170 000 predicted sequences, bacterial signal peptides represent one of the largest families of GPCR ligands and one of the most complex classes of natural activators of the innate immune system. By recognizing a conserved three-dimensional peptide motif, FPRs employ an unusual detection mechanism that combines structural promiscuity with high specificity and sensitivity, thus solving the problem of detecting thousands of distinct sequences yet maintaining selectivity. How signal peptides are released by bacteria and sensed by GPCRs and how these processes shape the responses of other cells and whole organisms represents an important topic for future research.

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Healthberry 865® and Its Related, Specific, Single Anthocyanins Exert a Direct Vascular Action, Modulating Both Endothelial Function and Oxidative Stress

Antioxidants ◽

10.3390/antiox10081191 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1191

Author(s):

Albino Carrizzo ◽

Rosario Lizio ◽

Paola Di Pietro ◽

Michele Ciccarelli ◽

Antonio Damato ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Nadph Oxidase ◽

Intracellular Signaling ◽

Vascular Reactivity ◽

Molecular Mechanisms ◽

Vascular Dysfunction ◽

Epidemiological Studies ◽

Direct Role ◽

And Oxidative Stress

In recent years, epidemiological studies have identified a relationship between diet and cerebro–cardiovascular disease (CVD). In this regard, there is a promising dietary group for cardiovascular protection are polyphenols, especially anthocyanins. Vascular reactivity studies were performed using Healthberry 865® and constituent single anthocyanins to characterize vasomotor responses; immunofluorescence analysis with dichlorofluorescein diacetate and dihydroethidium were used to evaluate nitric oxide and oxidative stress; lucigenin assay was used to measure NADPH oxidase activity; and gel electrophoresis and immunoblotting were used to dissect the molecular mechanisms involved. We demonstrated that Healthberry 865® exerts an important vasorelaxant effect of resistance artery functions in mice. Its action is mediated by nitric oxide release through the intracellular signaling PI3K/Akt. Moreover, behind its capability of modulating vascular tone, it also exerts an important antioxidant effect though the modulation of the NADPH oxidase enzyme. Interestingly, its cardiovascular properties are mediated by the selective action of different anthocyanins. Finally, the exposure of human dysfunctional vessels to Healthberry 865® significantly reduces oxidative stress and improves NO bioavailability. Although further investigations are needed, our data demonstrate the direct role of Healthberry 865® on the modulation of vasculature, both on the vasorelaxation and on oxidative stress; thus, supporting the concept that a pure mixture of anthocyanins could be helpful in preventing the onset of vascular dysfunction associated with the development of CVD.

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NADPH-oxidase activation in murine neutrophils via formyl peptide receptors

Experimental Cell Research ◽

10.1016/s0014-4827(02)00010-1 ◽

2003 ◽

Vol 282 (2) ◽

pp. 70-77 ◽

Cited By ~ 37

Author(s):

Johan Bylund ◽

Marie Samuelsson ◽

L.Vincent Collins ◽

Anna Karlsson

Keyword(s):

Nadph Oxidase ◽

Peptide Receptors ◽

Formyl Peptide Receptors ◽

Formyl Peptide ◽

Nadph Oxidase Activation

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The Two Formyl Peptide Receptors Differently Regulate GPR84-Mediated Neutrophil NADPH Oxidase Activity

Journal of Innate Immunity ◽

10.1159/000514887 ◽

2021 ◽

pp. 1-15

Author(s):

Jonas Mårtensson ◽

Martina Sundqvist ◽

Asmita Manandhar ◽

Loukas Leremias ◽

Linjie Zhang ◽

...

Keyword(s):

Nadph Oxidase ◽

Oxidase Activity ◽

G Protein Coupled Receptors ◽

Human Neutrophils ◽

Peptide Receptors ◽

Nadph Oxidase Activity ◽

Formyl Peptide Receptors ◽

Formyl Peptide ◽

Specific Antagonist ◽

G Protein Coupled

Neutrophils express the two formyl peptide receptors (FPR1 and FPR2) and the medium-chain fatty acid receptor GPR84. The FPRs are known to define a hierarchy among neutrophil G protein-coupled receptors (GPCRs), that is, the activated FPRs can either suppress or amplify GPCR responses. In this study, we investigated the position of GPR84 in the FPR-defined hierarchy regarding the activation of neutrophil nicotine adenine dinucleotide phosphate (NADPH) oxidase, an enzyme system designed to generate reactive oxygen species (ROS), which are important regulators in cell signaling and immune regulation. When resting neutrophils were activated by GPR84 agonists, a modest ROS release was induced. However, vast amounts of ROS were induced by these GPR84 agonists in FPR2-desensitized neutrophils, and the response was inhibited not only by a GPR84-specific antagonist but also by an FPR2-specific antagonist. This suggests that the amplified GPR84 agonist response is achieved through a reactivation of desensitized FPR2s. In addition, the GPR84-mediated FPR2 reactivation was independent of β-arrestin recruitment and sensitive to a protein phosphatase inhibitor. In contrast to FPR2-desensitized cells, FPR1 desensitization primarily resulted in a suppressed GPR84 agonist-induced ROS response, indicating a receptor hierarchical desensitization of GPR84 by FPR1-generated signals. In summary, our data show that the two FPRs in human neutrophils control the NADPH oxidase activity with concomitant ROS production by communicating with GPR84 through different mechanisms. While FPR1 desensitizes GPR84 and by that suppresses the release of ROS induced by GPR84 agonists, amplified ROS release is achieved by GPR84 agonists through reactivation of the desensitized FPR2.

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