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

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.

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

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.

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

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 243
Author(s):  
Valentina Maria Caso ◽  
Valentina Manzo ◽  
Tiziana Pecchillo Cimmino ◽  
Valeria Conti ◽  
Pio Caso ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Diseases ◽  
Nadph Oxidase ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Ros Production ◽  
Peptide Receptors ◽  
Formyl Peptide Receptors ◽  
Formyl Peptide ◽  
Anti Inflammatory

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.

Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects

Blood ◽  
2014 ◽  
Vol 124 (4) ◽  
pp. 590-597 ◽  
Author(s):  
Roel P. Gazendam ◽  
John L. van Hamme ◽  
Anton T. J. Tool ◽  
Michel van Houdt ◽  
Paul J. J. H. Verkuijlen ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Candida Albicans ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Human Neutrophils ◽  
Nadph Oxidase Activity ◽  
Key Points

Key Points Human neutrophils use 2 independent mechanisms for the killing of unopsonized and serum-opsonized C albicans. Unopsonized Candida killing depends on CR3 and CARD9 but not dectin-1; opsonized Candida killing on FcγR, PKC, and NADPH oxidase activity.

scholarly journals RhoA/Rho kinase mediates TGF-β1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species

2014 ◽  
Vol 307 (2) ◽  
pp. F159-F171 ◽  
Author(s):  
Nagaraj Manickam ◽  
Mandakini Patel ◽  
Kathy K. Griendling ◽  
Yves Gorin ◽  
Jeffrey L. Barnes
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Smooth Muscle Actin ◽  
Rho Kinase ◽  
Ros Generation ◽  
Myofibroblast Differentiation ◽  
Interacting Protein ◽  
Nadph Oxidase Activity

The small G proteins Rac1 and RhoA regulate actin cytoskeleton, cell shape, adhesion, migration, and proliferation. Recent studies in our laboratory have shown that NADPH oxidase Nox4-derived ROS are involved in transforming growth factor (TGF)-β1-induced rat kidney myofibroblast differentiation assessed by the acquisition of an α-smooth muscle actin (α-SMA) phenotype and expression of an alternatively spliced fibronectin variant (Fn-EIIIA). Rac1 and RhoA are essential in signaling by some Nox homologs, but their role as effectors of Nox4 in kidney myofibroblast differentiation is not known. In the present study, we explored a link among Rac1 and RhoA and Nox4-dependent ROS generation in TGF-β1-induced kidney myofibroblast activation. TGF-β1 stimulated an increase in Nox4 protein expression, NADPH oxidase activity, and abundant α-SMA and Fn-EIIIA expression. RhoA but not Rac1 was involved in TGF-β1 induction of Nox4 signaling of kidney myofibroblast activation. TGF-β1 stimulated active RhoA-GTP and increased Rho kinase (ROCK). Inhibition of RhoA with small interfering RNA and ROCK using Y-27632 significantly reduced TGF-β1-induced stimulation of Nox4 protein, NADPH oxidase activity, and α-SMA and Fn-EIIIA expression. Treatment with diphenyleneiodonium, an inhibitor of NADPH oxidase, did not decrease RhoA activation but inhibited TGF-β1-induced α-SMA and Fn-EIIIA expression, indicating that RhoA is upstream of ROS generation. RhoA/ROCK also regulated polymerase (DNA-directed) δ-interacting protein 2 (Poldip2), a newly discovered Nox4 enhancer protein. Collectively, these data indicate that RhoA/ROCK is upstream of Poldip2-dependent Nox4 regulation and ROS production and induces redox signaling of kidney myofibroblast activation and may broader implications in the pathophysiology of renal fibrosis.

scholarly journals Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

Blood ◽  
2013 ◽  
Vol 121 (11) ◽  
pp. 2099-2107 ◽  
Author(s):  
Alex George ◽  
Suvarnamala Pushkaran ◽  
Diamantis G. Konstantinidis ◽  
Sebastian Koochaki ◽  
Punam Malik ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Ros Production ◽  
Cell Disease ◽  
Nadph Oxidase Activity ◽  
Rac Gtpases ◽  
Key Points ◽  
Plasma Cytokines

Key Points Sickle RBC ROS production is mediated in part by NADPH oxidase activity. Sickle RBC ROS production can be induced by plasma signaling molecules.

scholarly journals Relation of human neutrophil phorbol ester receptor occupancy and NADPH- oxidase activity

Blood ◽  
1982 ◽  
Vol 60 (2) ◽  
pp. 333-339 ◽  
Author(s):  
AI Tauber ◽  
DB Brettler ◽  
EA Kennington ◽  
PM Blumberg
Keyword(s):  
Nadph Oxidase ◽  
Phorbol Ester ◽  
Respiratory Burst ◽  
Human Neutrophil ◽  
Oxidase Activity ◽  
Receptor Occupancy ◽  
Human Neutrophils ◽  
Binding Studies ◽  
Nadph Oxidase Activity ◽  
Phorbol Ester Receptor

Abstract Phorbol esters are potent stimulants of the respiratory burst of the human neutrophil as assessed by superoxide (O2-) generation in whole cells and by NADPH-oxidase activity in a broken-cell 27,000-g particulate fraction. Phorbol 12-myristate, 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDBu) stimulate production of O2- by human neutrophils with ED50 concentrations of 3.9 +/- 2.1 and 41.7 +/- 7.1 nM, respectively. The relation of biologic activity to receptor occupancy was assessed with binding studies of PMA and PDBu. Phorbol ester binding revealed a single high affinity phorbol ester receptor present at 7.6 x 10(5) sites/cell. The binding affinities for PMA and PDBu, 4.9 nM and 38.4 nM, respectively, agreed quantitatively with that of biologic potencies. Because of the high concentration of phorbol ester receptors (up to 125 nM) and the large amount of nonspecific binding at high cell density, apparent discrepancies between ED50′s for NADPH-oxidase and whole cell O2- generation were noted. With the use of low cell concentrations, quantitative agreement between intact cell production of O2-, NADPH-oxidase activity, and receptor binding was found. These results further support the identity of the NADPH-oxidase as the enzymatic source of respiratory burst O2- production in human neutrophils.

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

2003 ◽  
Vol 278 (33) ◽  
pp. 30578-30586 ◽  
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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