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 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 G-protein–coupled formyl peptide receptors play a dual role in neutrophil chemotaxis and bacterial phagocytosis

2019 ◽  
Vol 30 (3) ◽  
pp. 346-356 ◽  
Author(s):  
Xi Wen ◽  
Xuehua Xu ◽  
Wenxiang Sun ◽  
Keqiang Chen ◽  
Miao Pan ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Actin Polymerization ◽  
G Protein Coupled Receptors ◽  
Peptide Receptors ◽  
Tyrosine Kinase Signaling ◽  
Formyl Peptide Receptors ◽  
Formyl Peptide ◽  
G Protein Coupled

A dogma of innate immunity is that neutrophils use G-protein–coupled receptors (GPCRs) for chemoattractant to chase bacteria through chemotaxis and then use phagocytic receptors coupled with tyrosine kinases to destroy opsonized bacteria via phagocytosis. Our current work showed that G-protein–coupled formyl peptide receptors (FPRs) directly mediate neutrophil phagocytosis. Mouse neutrophils lacking formyl peptide receptors (Fpr1/2–/–) are defective in the phagocytosis of Escherichia coli and the chemoattractant N-formyl-Met-Leu-Phe (fMLP)-coated beads. fMLP immobilized onto the surface of a bead interacts with FPRs, which trigger a Ca2+response and induce actin polymerization to form a phagocytic cup for engulfment of the bead. This chemoattractant GPCR/Gi signaling works independently of phagocytic receptor/tyrosine kinase signaling to promote phagocytosis. Thus, in addition to phagocytic receptor-mediated phagocytosis, neutrophils also utilize the chemoattractant GPCR/Gi signaling to mediate phagocytosis to fight against invading bacteria.

scholarly journals Caulerpin Mitigates Helicobacter pylori-Induced Inflammation via Formyl Peptide Receptors

2021 ◽  
Vol 22 (23) ◽  
pp. 13154
Author(s):  
Paola Cuomo ◽  
Chiara Medaglia ◽  
Ivana Allocca ◽  
Angela Michela Immacolata Montone ◽  
Fabrizia Guerra ◽  
...  
Keyword(s):  
Immune Response ◽  
Helicobacter Pylori ◽  
Indole Alkaloid ◽  
G Protein Coupled Receptors ◽  
Innate Immune ◽  
Peptide Receptors ◽  
Formyl Peptide Receptors ◽  
Formyl Peptide ◽  
G Protein Coupled

The identification of novel strategies to control Helicobacter pylori (Hp)-associated chronic inflammation is, at present, a considerable challenge. Here, we attempt to combat this issue by modulating the innate immune response, targeting formyl peptide receptors (FPRs), G-protein coupled receptors that play key roles in both the regulation and the resolution of the innate inflammatory response. Specifically, we investigated, in vitro, whether Caulerpin—a bis-indole alkaloid isolated from algae of the genus Caulerpa—could act as a molecular antagonist scaffold of FPRs. We showed that Caulerpin significantly reduces the immune response against Hp culture filtrate, by reverting the FPR2-related signaling cascade and thus counteracting the inflammatory reaction triggered by Hp peptide Hp(2–20). Our study suggests Caulerpin to be a promising therapeutic or adjuvant agent for the attenuation of inflammation triggered by Hp infection, as well as its related adverse clinical outcomes.

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 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
Sign in / Sign up

Export Citation Format

Share Document