Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase
Phospholipases (PL) A<sub>2</sub> catalyzes the hydrolysis of membrane phospholipids and mostly generates arachidonic acid (AA). The enzyme 5-lipoxygenase (5-LOX) can metabolize AA to obtain inflammatory leukotrienes, whose biosynthesis highly depends on cPLA2 and 5-LOX activities. Formy...
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MDPI AG
2024-02-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/13/2/220 |
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| author | Tiziana Pecchillo Cimmino Iolanda Panico Simona Scarano Mariano Stornaiuolo Gabriella Esposito Rosario Ammendola Fabio Cattaneo |
| author_facet | Tiziana Pecchillo Cimmino Iolanda Panico Simona Scarano Mariano Stornaiuolo Gabriella Esposito Rosario Ammendola Fabio Cattaneo |
| author_sort | Tiziana Pecchillo Cimmino |
| collection | DOAJ |
| description | Phospholipases (PL) A<sub>2</sub> catalyzes the hydrolysis of membrane phospholipids and mostly generates arachidonic acid (AA). The enzyme 5-lipoxygenase (5-LOX) can metabolize AA to obtain inflammatory leukotrienes, whose biosynthesis highly depends on cPLA2 and 5-LOX activities. Formyl Peptide Receptor 2 (FPR2) belongs to a subfamily of class A GPCRs and is considered the most versatile FPRs isoform. Signaling triggered by FPR2 includes the activation of several downstream kinases and NADPH oxidase (NOX)-dependent ROS generation. In a metabolomic analysis we observed a significant increase in AA concentration in FPR2-stimulated lung cancer cell line CaLu-6. We analyzed cPLA2 phosphorylation and observed a time-dependent increase in cPLA2 Ser505 phosphorylation in FPR2-stimulated cells, which was prevented by the MEK inhibitor (PD098059) and the p38MAPK inhibitor (SB203580) and by blocking NOX function. Similarly, we demonstrated that phosphorylation of 5-LOX at Ser271 and Ser663 residues requires FPR2-dependent p38MAPK and ERKs activation. Moreover, we showed that 5-LOX Ser271 phosphorylation depends on a functional NOX expression. Our overall data demonstrate for the first time that FPR2-induced ERK- and p38MAPK-dependent phosphorylation/activation of cPLA2 and 5-LOX requires a functional NADPH oxidase. These findings represent an important step towards future novel therapeutic possibilities aimed at resolving the inflammatory processes underlying many human diseases. |
| first_indexed | 2024-03-07T22:44:12Z |
| format | Article |
| id | doaj.art-0bae0b4f317b4625ac7780321546336b |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-07T22:44:12Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-0bae0b4f317b4625ac7780321546336b2024-02-23T15:05:32ZengMDPI AGAntioxidants2076-39212024-02-0113222010.3390/antiox13020220Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH OxidaseTiziana Pecchillo Cimmino0Iolanda Panico1Simona Scarano2Mariano Stornaiuolo3Gabriella Esposito4Rosario Ammendola5Fabio Cattaneo6Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDepartment of Pharmacy, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyDepartment of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, ItalyPhospholipases (PL) A<sub>2</sub> catalyzes the hydrolysis of membrane phospholipids and mostly generates arachidonic acid (AA). The enzyme 5-lipoxygenase (5-LOX) can metabolize AA to obtain inflammatory leukotrienes, whose biosynthesis highly depends on cPLA2 and 5-LOX activities. Formyl Peptide Receptor 2 (FPR2) belongs to a subfamily of class A GPCRs and is considered the most versatile FPRs isoform. Signaling triggered by FPR2 includes the activation of several downstream kinases and NADPH oxidase (NOX)-dependent ROS generation. In a metabolomic analysis we observed a significant increase in AA concentration in FPR2-stimulated lung cancer cell line CaLu-6. We analyzed cPLA2 phosphorylation and observed a time-dependent increase in cPLA2 Ser505 phosphorylation in FPR2-stimulated cells, which was prevented by the MEK inhibitor (PD098059) and the p38MAPK inhibitor (SB203580) and by blocking NOX function. Similarly, we demonstrated that phosphorylation of 5-LOX at Ser271 and Ser663 residues requires FPR2-dependent p38MAPK and ERKs activation. Moreover, we showed that 5-LOX Ser271 phosphorylation depends on a functional NOX expression. Our overall data demonstrate for the first time that FPR2-induced ERK- and p38MAPK-dependent phosphorylation/activation of cPLA2 and 5-LOX requires a functional NADPH oxidase. These findings represent an important step towards future novel therapeutic possibilities aimed at resolving the inflammatory processes underlying many human diseases.https://www.mdpi.com/2076-3921/13/2/220arachidonic acidcell metabolismFormyl Peptide ReceptorFPR2NADPH oxidaseROS |
| spellingShingle | Tiziana Pecchillo Cimmino Iolanda Panico Simona Scarano Mariano Stornaiuolo Gabriella Esposito Rosario Ammendola Fabio Cattaneo Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase Antioxidants arachidonic acid cell metabolism Formyl Peptide Receptor FPR2 NADPH oxidase ROS |
| title | Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase |
| title_full | Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase |
| title_fullStr | Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase |
| title_full_unstemmed | Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase |
| title_short | Formyl Peptide Receptor 2-Dependent cPLA2 and 5-LOX Activation Requires a Functional NADPH Oxidase |
| title_sort | formyl peptide receptor 2 dependent cpla2 and 5 lox activation requires a functional nadph oxidase |
| topic | arachidonic acid cell metabolism Formyl Peptide Receptor FPR2 NADPH oxidase ROS |
| url | https://www.mdpi.com/2076-3921/13/2/220 |
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