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Huamei Forsman - One of the best experts on this subject based on the ideXlab platform.
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mitocryptides from human mitochondrial dna encoded proteins activate neutrophil Formyl Peptide Receptors receptor preference and signaling properties
Journal of Immunology, 2018Co-Authors: Michael Gabl, Andre Holdfeldt, Karin Christenson, Claes Dahlgren, Martina Sundqvist, Simon Lind, Jonas Martensson, Takayuki Marutani, Hidehito Mukai, Huamei ForsmanAbstract:Phagocytic neutrophils express Formyl Peptide Receptors (FPRs; FPR1 and FPR2) that distinctly recognize Peptides starting with an N-Formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA–encoded proteins is an fMet. Mitochondrial cryptic Peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs. In this study, we determined the neutrophil-recognition profiles and functional output of putative MCTs originating from the N termini of the 13 human mitochondrial DNA–encoded proteins. Six of the thirteen MCTs potently activated neutrophils with distinct FPR-recognition profiles: MCTs from ND3 and ND6 have a receptor preference for FPR1; MCTs from the proteins ND4, ND5, and cytochrome b prefer FPR2; and MCT-COX1 is a dual FPR1/FPR2 agonist. MCTs derived from ND2 and ND4L are very weak neutrophil activators, whereas MCTs from ND1, ATP6, ATP8, COX2, and COX3, do not exert agonistic or antagonistic FPR effects. In addition, the activating MCTs heterologously desensitized IL-8R but primed the response to the platelet-activating factor receptor agonist. More importantly, our data suggest that MCTs have biased signaling properties in favor of activation of the superoxide-generating NADPH oxidase or recruitment of β-arrestin. In summary, we identify several novel FPR-activating Peptides with sequences present in the N termini of mitochondrial DNA–encoded proteins, and our data elucidate the molecular basis of neutrophil activation by MCTs.
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Formyl Peptide Receptors in mice and men similarities and differences in recognition of conventional ligands and modulating lipoPeptides
Basic & Clinical Pharmacology & Toxicology, 2018Co-Authors: Malene Winther, Claes Dahlgren, Huamei ForsmanAbstract:The pattern recognition Formyl Peptide Receptors (FPRs) belong to the class of G protein-coupled Receptors (GPCRs), the largest group of cell-surface Receptors involved in a range of physiological processes and pathologies. The FPRs have regulatory function in the initiation as well as resolution of inflammatory reactions, making them highly interesting as targets for drug development. Recent research in the GPCR/FPR fields has uncovered novel receptor biology concepts, including biased signalling/functional selectivity, allosteric modulation, receptor reactivation and receptor cross-talk. When it comes to allosteric modulators, “tailor-made” lipoPeptides (pepducins and lipopeptoids) represent a novel concept of GPCR/FPR regulation. This MiniReview is focused on the basis for recognition of conventional ligands and immunomodulating lipopeptids, novel allosteric modulators for the FPRs, Receptors that are highly expressed by both human and mouse neutrophils. The FPRs play key roles in host defence against microbial infections, tissue homeostasis and the initiation as well as resolution of inflammation but there are both similarities and differences in ligand recognition between mice and men. Thus, identification and functional characterization of activating and inhibiting ligands should provide insights into future design of FPR-based animal models of human diseases and development of therapeutics for treating inflammatory diseases. This article is protected by copyright. All rights reserved.
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the role of Formyl Peptide Receptors for immunomodulatory activities of antimicrobial Peptides and peptidomimetics
Current Pharmaceutical Design, 2018Co-Authors: Sarah Line Skovbakke, Andre Holdfeldt, Huamei Forsman, Johan Bylund, Henrik FranzykAbstract:: 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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a novel receptor cross talk between the atp receptor p2y2 and Formyl Peptide Receptors reactivates desensitized neutrophils to produce superoxide
Experimental Cell Research, 2014Co-Authors: Karin Onnheim, Johan Bylund, Karin Christenson, Michael Gabl, Joachim C Burbiel, Christa E Muller, Tudor I Oprea, Claes Dahlgren, Huamei ForsmanAbstract:Abstract Neutrophils express several G-protein coupled Receptors (GPCRs) and they cross regulate each other. We described a novel cross-talk mechanism in neutrophils, by which signals generated by the receptor for ATP (P2Y2) reactivate desensitized Formyl Peptide Receptors (FPRs) so that these ligand-bound inactive FPRs resume signaling. At the signaling level, the cross-talk was unidirectional, i.e., P2Y2 ligation reactivated FPR, but not vice versa and was sensitive to the phosphatase inhibitor calyculinA. Further, we show that the cross talk between P2Y2 and FPR bypassed cytosolic Ca2+ transients and did not rely on the actin cytoskeleton. In summary, our data demonstrate a novel cross-talk mechanism that results in reactivation of desensitized FPRs and, an amplification of the neutrophil response to ATP.
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reactivation of desensitized Formyl Peptide Receptors by platelet activating factor a novel receptor cross talk mechanism regulating neutrophil superoxide anion production
PLOS ONE, 2013Co-Authors: Huamei Forsman, Johan Bylund, Karin Onnheim, Karin Christenson, Anna Karlsson, Emil Andreasson, Claes DahlgrenAbstract:Neutrophils express different chemoattractant Receptors of importance for guiding the cells from the blood stream to sites of inflammation. These Receptors communicate with one another, a cross talk manifested as hierarchical, heterologous receptor desensitization. We describe a new receptor cross talk mechanism, by which desensitized Formyl Peptide Receptors (FPRdes) can be reactivated. FPR desensitization is induced through binding of specific FPR agonists and is reached after a short period of active signaling. The mechanism that transfers the receptor to a non-signaling desensitized state is not known, and a signaling pathway has so far not been described, that transfers FPRdes back to an active signaling state. The reactivation signal was generated by PAF stimulation of its receptor (PAFR) and the cross talk was uni-directional. LatrunculinA, an inhibitor of actin polymerization, induced a similar reactivation of FPRdes as PAF while the phosphatase inhibitor CalyculinA inhibited reactivation, suggesting a role for the actin cytoskeleton in receptor desensitization and reactivation. The activated PAFR could, however, reactivate FPRdes also when the cytoskeleton was disrupted prior to activation. The receptor cross talk model presented prophesies that the contact on the inner leaflet of the plasma membrane that blocks signaling between the G-protein and the FPR is not a point of no return; the receptor cross-talk from the PAFRs to the FPRdes initiates an actin-independent signaling pathway that turns desensitized Receptors back to a signaling state. This represents a novel mechanism for amplification of neutrophil production of reactive oxygen species.
Claes Dahlgren - One of the best experts on this subject based on the ideXlab platform.
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mitocryptides from human mitochondrial dna encoded proteins activate neutrophil Formyl Peptide Receptors receptor preference and signaling properties
Journal of Immunology, 2018Co-Authors: Michael Gabl, Andre Holdfeldt, Karin Christenson, Claes Dahlgren, Martina Sundqvist, Simon Lind, Jonas Martensson, Takayuki Marutani, Hidehito Mukai, Huamei ForsmanAbstract:Phagocytic neutrophils express Formyl Peptide Receptors (FPRs; FPR1 and FPR2) that distinctly recognize Peptides starting with an N-Formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA–encoded proteins is an fMet. Mitochondrial cryptic Peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs. In this study, we determined the neutrophil-recognition profiles and functional output of putative MCTs originating from the N termini of the 13 human mitochondrial DNA–encoded proteins. Six of the thirteen MCTs potently activated neutrophils with distinct FPR-recognition profiles: MCTs from ND3 and ND6 have a receptor preference for FPR1; MCTs from the proteins ND4, ND5, and cytochrome b prefer FPR2; and MCT-COX1 is a dual FPR1/FPR2 agonist. MCTs derived from ND2 and ND4L are very weak neutrophil activators, whereas MCTs from ND1, ATP6, ATP8, COX2, and COX3, do not exert agonistic or antagonistic FPR effects. In addition, the activating MCTs heterologously desensitized IL-8R but primed the response to the platelet-activating factor receptor agonist. More importantly, our data suggest that MCTs have biased signaling properties in favor of activation of the superoxide-generating NADPH oxidase or recruitment of β-arrestin. In summary, we identify several novel FPR-activating Peptides with sequences present in the N termini of mitochondrial DNA–encoded proteins, and our data elucidate the molecular basis of neutrophil activation by MCTs.
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Formyl Peptide Receptors in mice and men similarities and differences in recognition of conventional ligands and modulating lipoPeptides
Basic & Clinical Pharmacology & Toxicology, 2018Co-Authors: Malene Winther, Claes Dahlgren, Huamei ForsmanAbstract:The pattern recognition Formyl Peptide Receptors (FPRs) belong to the class of G protein-coupled Receptors (GPCRs), the largest group of cell-surface Receptors involved in a range of physiological processes and pathologies. The FPRs have regulatory function in the initiation as well as resolution of inflammatory reactions, making them highly interesting as targets for drug development. Recent research in the GPCR/FPR fields has uncovered novel receptor biology concepts, including biased signalling/functional selectivity, allosteric modulation, receptor reactivation and receptor cross-talk. When it comes to allosteric modulators, “tailor-made” lipoPeptides (pepducins and lipopeptoids) represent a novel concept of GPCR/FPR regulation. This MiniReview is focused on the basis for recognition of conventional ligands and immunomodulating lipopeptids, novel allosteric modulators for the FPRs, Receptors that are highly expressed by both human and mouse neutrophils. The FPRs play key roles in host defence against microbial infections, tissue homeostasis and the initiation as well as resolution of inflammation but there are both similarities and differences in ligand recognition between mice and men. Thus, identification and functional characterization of activating and inhibiting ligands should provide insights into future design of FPR-based animal models of human diseases and development of therapeutics for treating inflammatory diseases. This article is protected by copyright. All rights reserved.
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a novel receptor cross talk between the atp receptor p2y2 and Formyl Peptide Receptors reactivates desensitized neutrophils to produce superoxide
Experimental Cell Research, 2014Co-Authors: Karin Onnheim, Johan Bylund, Karin Christenson, Michael Gabl, Joachim C Burbiel, Christa E Muller, Tudor I Oprea, Claes Dahlgren, Huamei ForsmanAbstract:Abstract Neutrophils express several G-protein coupled Receptors (GPCRs) and they cross regulate each other. We described a novel cross-talk mechanism in neutrophils, by which signals generated by the receptor for ATP (P2Y2) reactivate desensitized Formyl Peptide Receptors (FPRs) so that these ligand-bound inactive FPRs resume signaling. At the signaling level, the cross-talk was unidirectional, i.e., P2Y2 ligation reactivated FPR, but not vice versa and was sensitive to the phosphatase inhibitor calyculinA. Further, we show that the cross talk between P2Y2 and FPR bypassed cytosolic Ca2+ transients and did not rely on the actin cytoskeleton. In summary, our data demonstrate a novel cross-talk mechanism that results in reactivation of desensitized FPRs and, an amplification of the neutrophil response to ATP.
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further studies on 2 arylacetamide pyridazin 3 2h ones design synthesis and evaluation of 4 6 disubstituted analogs as Formyl Peptide Receptors fprs agonists
European Journal of Medicinal Chemistry, 2013Co-Authors: Maria Paola Giovannoni, Andrei I. Khlebnikov, Igor A. Schepetkin, Agostino Cilibrizzi, Letizia Crocetti, Liliya N Kirpotina, Claes Dahlgren, Alessia Graziano, Vittorio Dal Piaz, Serena ZerbinatiAbstract:Formyl Peptide Receptors (FPRs) play an essential role in the regulation of endogenous inflammation and immunity. In the present studies, a large series of pyridazin-3(2H)-one derivatives bearing an arylacetamide chain at position 2 was synthesized and tested for FPR agonist activity. The pyridazin-3(2H)-one ring was confirmed to be an appropriate scaffold to support FPR agonist activity, and its modification at the 4 and 6 positions led to the identification of additional active agonists, which induced intracellular Ca2+ flux in HL-60 cells transfected with either FPR1, FPR2, or FPR3. Seven Formyl Peptide receptor 1 (FPR1)-specific and several mixed FPR1/FPR2 dual agonists were identified with low micromolar EC50 values. Furthermore, these agonists also activated human neutrophils, inducing intracellular Ca2+ flux and chemotaxis. Finally, molecular docking studies indicated that the most potent pyridazin-3(2H)-ones overlapped in their best docking poses with fMLF and WKYMVM Peptides in the FPR1 and FPR2 ligand binding sites, respectively. Thus, pyridazinone-based compounds represent potential lead compounds for further development of selective and/or potent FPR agonists.
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reactivation of desensitized Formyl Peptide Receptors by platelet activating factor a novel receptor cross talk mechanism regulating neutrophil superoxide anion production
PLOS ONE, 2013Co-Authors: Huamei Forsman, Johan Bylund, Karin Onnheim, Karin Christenson, Anna Karlsson, Emil Andreasson, Claes DahlgrenAbstract:Neutrophils express different chemoattractant Receptors of importance for guiding the cells from the blood stream to sites of inflammation. These Receptors communicate with one another, a cross talk manifested as hierarchical, heterologous receptor desensitization. We describe a new receptor cross talk mechanism, by which desensitized Formyl Peptide Receptors (FPRdes) can be reactivated. FPR desensitization is induced through binding of specific FPR agonists and is reached after a short period of active signaling. The mechanism that transfers the receptor to a non-signaling desensitized state is not known, and a signaling pathway has so far not been described, that transfers FPRdes back to an active signaling state. The reactivation signal was generated by PAF stimulation of its receptor (PAFR) and the cross talk was uni-directional. LatrunculinA, an inhibitor of actin polymerization, induced a similar reactivation of FPRdes as PAF while the phosphatase inhibitor CalyculinA inhibited reactivation, suggesting a role for the actin cytoskeleton in receptor desensitization and reactivation. The activated PAFR could, however, reactivate FPRdes also when the cytoskeleton was disrupted prior to activation. The receptor cross talk model presented prophesies that the contact on the inner leaflet of the plasma membrane that blocks signaling between the G-protein and the FPR is not a point of no return; the receptor cross-talk from the PAFRs to the FPRdes initiates an actin-independent signaling pathway that turns desensitized Receptors back to a signaling state. This represents a novel mechanism for amplification of neutrophil production of reactive oxygen species.
Johan Bylund - One of the best experts on this subject based on the ideXlab platform.
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the role of Formyl Peptide Receptors for immunomodulatory activities of antimicrobial Peptides and peptidomimetics
Current Pharmaceutical Design, 2018Co-Authors: Sarah Line Skovbakke, Andre Holdfeldt, Huamei Forsman, Johan Bylund, Henrik FranzykAbstract:: 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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a novel receptor cross talk between the atp receptor p2y2 and Formyl Peptide Receptors reactivates desensitized neutrophils to produce superoxide
Experimental Cell Research, 2014Co-Authors: Karin Onnheim, Johan Bylund, Karin Christenson, Michael Gabl, Joachim C Burbiel, Christa E Muller, Tudor I Oprea, Claes Dahlgren, Huamei ForsmanAbstract:Abstract Neutrophils express several G-protein coupled Receptors (GPCRs) and they cross regulate each other. We described a novel cross-talk mechanism in neutrophils, by which signals generated by the receptor for ATP (P2Y2) reactivate desensitized Formyl Peptide Receptors (FPRs) so that these ligand-bound inactive FPRs resume signaling. At the signaling level, the cross-talk was unidirectional, i.e., P2Y2 ligation reactivated FPR, but not vice versa and was sensitive to the phosphatase inhibitor calyculinA. Further, we show that the cross talk between P2Y2 and FPR bypassed cytosolic Ca2+ transients and did not rely on the actin cytoskeleton. In summary, our data demonstrate a novel cross-talk mechanism that results in reactivation of desensitized FPRs and, an amplification of the neutrophil response to ATP.
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reactivation of desensitized Formyl Peptide Receptors by platelet activating factor a novel receptor cross talk mechanism regulating neutrophil superoxide anion production
PLOS ONE, 2013Co-Authors: Huamei Forsman, Johan Bylund, Karin Onnheim, Karin Christenson, Anna Karlsson, Emil Andreasson, Claes DahlgrenAbstract:Neutrophils express different chemoattractant Receptors of importance for guiding the cells from the blood stream to sites of inflammation. These Receptors communicate with one another, a cross talk manifested as hierarchical, heterologous receptor desensitization. We describe a new receptor cross talk mechanism, by which desensitized Formyl Peptide Receptors (FPRdes) can be reactivated. FPR desensitization is induced through binding of specific FPR agonists and is reached after a short period of active signaling. The mechanism that transfers the receptor to a non-signaling desensitized state is not known, and a signaling pathway has so far not been described, that transfers FPRdes back to an active signaling state. The reactivation signal was generated by PAF stimulation of its receptor (PAFR) and the cross talk was uni-directional. LatrunculinA, an inhibitor of actin polymerization, induced a similar reactivation of FPRdes as PAF while the phosphatase inhibitor CalyculinA inhibited reactivation, suggesting a role for the actin cytoskeleton in receptor desensitization and reactivation. The activated PAFR could, however, reactivate FPRdes also when the cytoskeleton was disrupted prior to activation. The receptor cross talk model presented prophesies that the contact on the inner leaflet of the plasma membrane that blocks signaling between the G-protein and the FPR is not a point of no return; the receptor cross-talk from the PAFRs to the FPRdes initiates an actin-independent signaling pathway that turns desensitized Receptors back to a signaling state. This represents a novel mechanism for amplification of neutrophil production of reactive oxygen species.
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ligand recognition and activation of Formyl Peptide Receptors in neutrophils
Journal of Leukocyte Biology, 2006Co-Authors: Huamei Fu, Johan Bylund, Anna Karlsson, Jennie Karlsson, Charlotta Movitz, Claes DahlgrenAbstract:Neutrophil granulocytes, professional phagocytes of the innate immune system, can migrate in response to gradients of chemoattractants, soluble molecules serving as “danger signals.” The chemotactic behavior of these cells is of great importance for the outcome of the continuously ongoing combat with invading microorganisms. In a number of inflammatory disorders, the chemoattractant-guided accumulation of neutrophils and their subsequent release of reactive oxygen species (ROS) and proteolytic enzymes are responsible for the tissue damage associated with such disease conditions. Research about the structure and function of neutrophil chemoattractants and their Receptors is therefore of direct clinical importance and relevance. Although chemotaxis was defined already as an important part of active immune reactivity already by Elie Metchnikoff in the late 19th century [1], the modern chemotaxis research era started first, by the introduction of a filter technique in 1962 [2], which allowed quantitative determinations of neutrophil migration and a rational search for specific attractants derived from intruding microbes or activated/damaged host cells [3]. Following the discovery of bacteria-derived, Formylated Peptides as potent neutrophil chemoattractants in the mid-1970s [4], the list of structurally well-characterized leukocyte chemoattractants has steadily grown. Other microbial components, cleavage products from the complement system (e.g., C5a), lipid metabolites such as platelet-activating factor (PAF) and leukotriene B4 (LTB4), as well as a large group of chemokines are examples of such molecules [5] (Table 1). During the last two decades, a broad application of molecular biology techniques has also led to identification of the chemoattractant Receptors. Despite the fact that these Receptors recognize different chemoattractants specifically, they exhibit some sequence homologies and share structural features, all belonging to a pertussis toxin (PTX)-sensitive subfamily within the G protein-coupled receptor (GPCR) superfamily. The reader is referred to several excellent review articles, which in more detail, discuss general aspects of the chemoattractant receptor family and neutrophil activation in inflammation [5 –7, 16]. We intend to summarize the current knowledge about structure and function of two closely related neutrophil G proteincoupled chemoattractant Receptors: the FPR, which was the first characterized member in the FPR family, and the closely related FPRL1, also called LXA4 receptor, as this eicosanoid was the first specific agonist described for the receptor. A large number of agonists for these Receptors have now been identified, and the same basic neutrophil functional responses are triggered by ligation of these Receptors [16]—chemotaxis, receptor mobilization, secretion of proteolytic enzymes and inflammatory mediators, and production of ROS. Ligand recognition by the two neutrophil FPR, linked to activation and signaling, is the subject of this review.
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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, 2003Co-Authors: Johan Bylund, Ase Bjorstad, Daniel Granfeldt, Anna Karlsson, Charlotte Woschnagg, Claes DahlgrenAbstract:Abstract In neutrophils, coupling of chemoattractants to their cell surface receptor at low temperature (≤15 °C) leads to receptor deactivation/desensitization without any triggering of the superoxide anion-generating NADPH-oxidase. We show that the deactivated Formyl Peptide Receptors (FPRs) can be reactivated/resensitized by the cytoskeleton-disrupting drug cytochalasin B. Such cytoskeleton-dependent receptor reactivation occurs also with the closely related Receptors FPR-like-1 and C5aR but not with the Receptors for interleukin-8 and platelet-activating factor. The reactivation state was further characterized with FPR as a model. The signals generated by receptor reactivation induced superoxide production that was terminated in 5–8 min, after which the neutrophils entered a new state of homologous deactivation. FPR antagonists were potent inhibitors of the superoxide production induced by the reactivated Receptors, suggesting that the occupied Receptors turn into an actively signaling state when the cytoskeleton is disrupted. The signals generated by the reactivated receptor were pertussis toxin-sensitive, indicating involvement of a G-protein. However, no transient elevation of intracellular Ca2+ accompanies the NADPH-oxidase activation. This was not due to a general down-regulation of phospholipase C/Ca2+ signaling, and despite the fact that no intracellular Ca2+ transient was generated, protein kinase C still appeared to be involved in the response. Further, phosphatidylinositol 3-kinase, mitogen-activated protein kinase, and MEK all participated in the generation of second messengers from the reactivated Receptors.
A De Paulis - One of the best experts on this subject based on the ideXlab platform.
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role of Formyl Peptide Receptors in gastrointestinal healing
Current Pharmaceutical Design, 2018Co-Authors: Nella Prevete, A De Paulis, D Sgambato, Rosa Marina Melillo, G D Argenio, L Romano, R M Zagari, M RomanoAbstract:: The wound healing and the barrier restoration of the gastrointestinal (GI) mucosa must be continuously ensured to allow homeostasis of the gastrointestinal tract and of all the surrounding tissues. Several lines of the evidence report a key role of innate immunity, and in particular of Pattern Recognition Receptors (PRRs), in controlling the homeostasis of GI tract by sensing commensal and pathogen bacteria, activating the immune response and regulating epithelial repair, thus guaranteeing the morphological and functional recovery of the injured tissue. We will discuss the role of a particular class of PRRs - the Formyl Peptide Receptors - in the homeostasis of GI mucosa. We here report the results of studies that strongly suggest the possibility that the activation of FPRs is crucial in the maintenance of homeostasis of the GI tract and provide indications of the potential clinical relevance of new treatment regimens involving FPR modulation for several GI disorders.
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Formyl Peptide Receptors at the interface of inflammation angiogenesis and tumor growth
Pharmacological Research, 2015Co-Authors: Nella Prevete, Rosa Marina Melillo, Federica Liotti, Gianni Marone, A De PaulisAbstract:Abstract N -Formyl Peptide Receptors (FPRs) belong to the family of pattern recognition Receptors (PRRs) that regulate innate immune responses. Three FPRs have been identified in humans: FPR1–FPR3. FPR expression was initially described in immune cells and subsequently in non-hematopoietic cells and certain tissues. Besides their involvement in inflammatory disorders, FPRs have been implicated in the regulation of tissue repair and angiogenesis. Angiogenesis is not only a key component of pathogen defence during acute infection and of chronic inflammatory disorders, but also plays a critical role in wound healing and tissue regeneration. Moreover, pathologic uncontrolled angiogenesis is central for tumour growth, progression, and the formation of metastases. In this review, we summarise the evidence for a central role of FPRs at the intersection between inflammation, physiologic angiogenesis and pathologic neovascularisation linked to cancer. These findings provide insights into the potential clinical relevance of new treatment regimens involving FPR modulation.
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helicobacter pylori hp 2 20 promotes migration and proliferation of gastric epithelial cells by interacting with Formyl Peptide Receptors in vitro and accelerates gastric mucosal healing in vivo
Journal of Immunology, 2009Co-Authors: A De Paulis, Nella Prevete, Francesca Wanda Rossi, Felice Rivellese, Fiamma Salerno, Gabriele Delfino, Bianca Liccardo, Elvira Avilla, Nunzia Montuori, Massimo MascoloAbstract:Helicobacter pylori-derived Peptide RpL1 aa 2-20 (Hp(2-20)) in addition to its antimicrobial action exerts several immunomodulatory effects in eukaryotic cells by interacting with Formyl Peptide Receptors (FPRs). It has recently been shown that activation of FPRs facilitates intestinal epithelial cell restitution. We investigated whether Hp(2-20) induces healing of injured gastric mucosa and assessed the mechanisms underlying any such effect. We investigated the expression of FPRs in two gastric epithelial cell lines (MKN-28 and AGS) at mRNA and protein level. To determine whether FPRs were functional we performed chemotaxis experiments and proliferation assays and studied the Hp(2-20)-activated downstream signaling pathway. The effect of Hp(2-20) on mucosal healing was evaluated in rats after indomethacin-induced injury. Here we show that: (1) FPRs were expressed in both cell lines; (2) Hp(2-20) stimulated migration and proliferation of gastric epithelial cells; (3) this effect was specifically mediated by Formyl Peptide receptor-like 1 (FPRL1) and FPRL2 and was associated with activation of FPR-related downstream signaling pathways; (4) Hp(2-20) up-regulated the expression and secretion of vascular endothelial growth factor; and (5) Hp(2-20) accelerated healing of rat gastric mucosa after injury brought about by indomethacin at both the macroscopic and microscopic levels. In conclusion, by interacting with FRPL1 and FPRL2, H. pylori-derived Hp(2-20) induces cell migration and proliferation, as well as the expression of vascular endothelial growth factor, thereby promoting gastric mucosal healing. This study provides further evidence of the complexity of the relationship between H. pylori and human gastric mucosa, and it suggests that a bacterial product may be used to heal gastric mucosal injury.
Nella Prevete - One of the best experts on this subject based on the ideXlab platform.
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role of Formyl Peptide Receptors in gastrointestinal healing
Current Pharmaceutical Design, 2018Co-Authors: Nella Prevete, A De Paulis, D Sgambato, Rosa Marina Melillo, G D Argenio, L Romano, R M Zagari, M RomanoAbstract:: The wound healing and the barrier restoration of the gastrointestinal (GI) mucosa must be continuously ensured to allow homeostasis of the gastrointestinal tract and of all the surrounding tissues. Several lines of the evidence report a key role of innate immunity, and in particular of Pattern Recognition Receptors (PRRs), in controlling the homeostasis of GI tract by sensing commensal and pathogen bacteria, activating the immune response and regulating epithelial repair, thus guaranteeing the morphological and functional recovery of the injured tissue. We will discuss the role of a particular class of PRRs - the Formyl Peptide Receptors - in the homeostasis of GI mucosa. We here report the results of studies that strongly suggest the possibility that the activation of FPRs is crucial in the maintenance of homeostasis of the GI tract and provide indications of the potential clinical relevance of new treatment regimens involving FPR modulation for several GI disorders.
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Formyl Peptide Receptors at the interface of inflammation angiogenesis and tumor growth
Pharmacological Research, 2015Co-Authors: Nella Prevete, Rosa Marina Melillo, Federica Liotti, Gianni Marone, A De PaulisAbstract:Abstract N -Formyl Peptide Receptors (FPRs) belong to the family of pattern recognition Receptors (PRRs) that regulate innate immune responses. Three FPRs have been identified in humans: FPR1–FPR3. FPR expression was initially described in immune cells and subsequently in non-hematopoietic cells and certain tissues. Besides their involvement in inflammatory disorders, FPRs have been implicated in the regulation of tissue repair and angiogenesis. Angiogenesis is not only a key component of pathogen defence during acute infection and of chronic inflammatory disorders, but also plays a critical role in wound healing and tissue regeneration. Moreover, pathologic uncontrolled angiogenesis is central for tumour growth, progression, and the formation of metastases. In this review, we summarise the evidence for a central role of FPRs at the intersection between inflammation, physiologic angiogenesis and pathologic neovascularisation linked to cancer. These findings provide insights into the potential clinical relevance of new treatment regimens involving FPR modulation.
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role s of Formyl Peptide Receptors expressed in nasal epithelial cells
Journal of Biological Regulators and Homeostatic Agents, 2011Co-Authors: Nella Prevete, Gianni Marone, Francesco Antonio Salzano, Francesca Wanda Rossi, Felice Rivellese, Massimo Dellepiane, Luca Guastini, Renzo Mora, Angelo Salami, De Paulis AAbstract:Abstract Chronic rhinosinusitis is one of the most frequent chronic diseases in humans. Little is known about stimuli initiating tissue remodeling process that determines the morphological expression of the disease. N-Formyl Peptide Receptors (FPRs) are innate immunity Receptors important in tissue remodeling of gastric and intestinal epithelium. The expression and functions of FPRs in nasal epithelial cells were examined to evaluate whether they could be important in the remodeling of nasal mucosa. The aim of this study is to examine FPR expression in a nasal epithelial cell line (RPMI-2650) at mRNA and protein levels. To determine whether FPRs were functional, chemotaxis experiments were carried out. In addition the effects of FPRs agonists on the expression (PCR and ELISA) of VEGF-A and TGF-beta, two key mediators of tissue remodelling, were examined. Here we demonstrate that RPMI-2650 express FPR and FPRL2, but not FPRL1. fMLP, a bacterial product active on FPR, and uPAR(84-95), an inflammatory mediator agonist for FPRL2, stimulated migration of nasal epithelial cells. fMLP and uPAR(84-95) induce expression and secretion of VEGF-A and TGF-beta. Our results suggest a possible mechanisms initiating tissue remodeling observed during chronic rhinosinusitis. This study provides further evidence that FPRs play a more complex role in human pathophysiology than bacterial recognition.
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helicobacter pylori hp 2 20 promotes migration and proliferation of gastric epithelial cells by interacting with Formyl Peptide Receptors in vitro and accelerates gastric mucosal healing in vivo
Journal of Immunology, 2009Co-Authors: A De Paulis, Nella Prevete, Francesca Wanda Rossi, Felice Rivellese, Fiamma Salerno, Gabriele Delfino, Bianca Liccardo, Elvira Avilla, Nunzia Montuori, Massimo MascoloAbstract:Helicobacter pylori-derived Peptide RpL1 aa 2-20 (Hp(2-20)) in addition to its antimicrobial action exerts several immunomodulatory effects in eukaryotic cells by interacting with Formyl Peptide Receptors (FPRs). It has recently been shown that activation of FPRs facilitates intestinal epithelial cell restitution. We investigated whether Hp(2-20) induces healing of injured gastric mucosa and assessed the mechanisms underlying any such effect. We investigated the expression of FPRs in two gastric epithelial cell lines (MKN-28 and AGS) at mRNA and protein level. To determine whether FPRs were functional we performed chemotaxis experiments and proliferation assays and studied the Hp(2-20)-activated downstream signaling pathway. The effect of Hp(2-20) on mucosal healing was evaluated in rats after indomethacin-induced injury. Here we show that: (1) FPRs were expressed in both cell lines; (2) Hp(2-20) stimulated migration and proliferation of gastric epithelial cells; (3) this effect was specifically mediated by Formyl Peptide receptor-like 1 (FPRL1) and FPRL2 and was associated with activation of FPR-related downstream signaling pathways; (4) Hp(2-20) up-regulated the expression and secretion of vascular endothelial growth factor; and (5) Hp(2-20) accelerated healing of rat gastric mucosa after injury brought about by indomethacin at both the macroscopic and microscopic levels. In conclusion, by interacting with FRPL1 and FPRL2, H. pylori-derived Hp(2-20) induces cell migration and proliferation, as well as the expression of vascular endothelial growth factor, thereby promoting gastric mucosal healing. This study provides further evidence of the complexity of the relationship between H. pylori and human gastric mucosa, and it suggests that a bacterial product may be used to heal gastric mucosal injury.