N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis, alteration in the microvasculature and immunologic abnormalities. It has been hypothesized that an abnormal redox state could regulate the persistent fibrotic phenotype in SSc patients. N-Formyl peptide receptors (FP...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00574/full |
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| author | Filomena Napolitano Francesca Wanda Rossi Francesca Wanda Rossi Ada Pesapane Silvia Varricchio Gennaro Ilardi Massimo Mascolo Stefania Staibano Antonio Lavecchia Pia Ragno Carmine Selleri Gianni Marone Gianni Marone Gianni Marone Marco Matucci-Cerinic Marco Matucci-Cerinic Amato de Paulis Amato de Paulis Nunzia Montuori Nunzia Montuori |
| author_facet | Filomena Napolitano Francesca Wanda Rossi Francesca Wanda Rossi Ada Pesapane Silvia Varricchio Gennaro Ilardi Massimo Mascolo Stefania Staibano Antonio Lavecchia Pia Ragno Carmine Selleri Gianni Marone Gianni Marone Gianni Marone Marco Matucci-Cerinic Marco Matucci-Cerinic Amato de Paulis Amato de Paulis Nunzia Montuori Nunzia Montuori |
| author_sort | Filomena Napolitano |
| collection | DOAJ |
| description | Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis, alteration in the microvasculature and immunologic abnormalities. It has been hypothesized that an abnormal redox state could regulate the persistent fibrotic phenotype in SSc patients. N-Formyl peptide receptors (FPRs) are chemotactic receptors overexpressed in fibroblasts derived from SSc patients. In this study, we demonstrated that stimulation of FPRs promotes the generation of reactive oxygen species (ROS) in skin fibroblasts. In fibroblast cells, ROS production was due to FPRs interaction with the urokinase receptor (uPAR) and to β1 integrin engagement. FPRs cross-talk with uPAR and integrins led to Rac1 and ERKs activation. FPRs stimulation increased gp91phox and p67phox expression as well as the direct interaction between GTP-Rac1 and p67phox, thus promoting assembly and activation of the NADPH oxidase complex. FPRs functions occur through interaction with a specific domain of uPAR (residues 88SRSRY92) that can be exposed on the cell membrane by protease-mediated receptor cleavage. Immunohistochemistry analysis with a specific anti-SRSRY antibody showed increased expression of uPAR in a cleaved form, which exposes the SRSRY sequence at its N-terminus (DIIDIII-uPAR88–92) in skin biopsies from SSc patients. As expected by the increased expression of both FPRs and DII-DIII-uPAR88-92, fibroblasts derived from SSc patients showed a significantly increase in ROS generation both at a basal level than after FPRs stimulation, as compared to fibroblasts from normal subjects. C37, a small molecule blocking the interaction between FPRs and uPAR, and selumetinib, a clinically approved MAPKK/ERK inhibitor, significantly inhibited FPRs-mediated ROS production in fibroblasts derived from SSc patients. Thus, FPRs, through the interaction with the uPA/uPAR system, can induce ROS generation in fibroblasts by activating the NADPH oxidase, playing a role in the alteration of the redox state observed in SSc. |
| first_indexed | 2024-12-21T12:21:38Z |
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| id | doaj.art-b647a0e0c8754ef385d4c6d6bcdbf5cd |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T12:21:38Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b647a0e0c8754ef385d4c6d6bcdbf5cd2022-12-21T19:04:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-04-01910.3389/fimmu.2018.00574324242N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase ReceptorFilomena Napolitano0Francesca Wanda Rossi1Francesca Wanda Rossi2Ada Pesapane3Silvia Varricchio4Gennaro Ilardi5Massimo Mascolo6Stefania Staibano7Antonio Lavecchia8Pia Ragno9Carmine Selleri10Gianni Marone11Gianni Marone12Gianni Marone13Marco Matucci-Cerinic14Marco Matucci-Cerinic15Amato de Paulis16Amato de Paulis17Nunzia Montuori18Nunzia Montuori19Department of Translational Medical Sciences, University of Naples Federico II, Naples, ItalyDepartment of Translational Medical Sciences, University of Naples Federico II, Naples, ItalyCenter for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Naples, ItalyDepartment of Translational Medical Sciences, University of Naples Federico II, Naples, ItalyDepartment of Advanced Functional Sciences, Pathology Section, University of Naples Federico II, Naples, ItalyDepartment of Advanced Functional Sciences, Pathology Section, University of Naples Federico II, Naples, ItalyDepartment of Advanced Functional Sciences, Pathology Section, University of Naples Federico II, Naples, ItalyDepartment of Advanced Functional Sciences, Pathology Section, University of Naples Federico II, Naples, ItalyDepartment of Pharmacy, Drug Discovery Laboratory, University of Naples Federico II, Naples, ItalyDepartment of Chemistry and Biology, University of Salerno, Salerno, ItalyDepartment of Medicine and Surgery, University of Salerno, Salerno, ItalyDepartment of Translational Medical Sciences, University of Naples Federico II, Naples, ItalyCenter for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Naples, ItalyInstitute of Experimental Endocrinology and Oncology (IEOS), Consiglio Nazionale delle Ricerche (CNR), Naples, ItalyDepartment of Experimental and Clinical Medicine, University of Florence, Florence, ItalyDepartment of Geriatric Medicine, Division of Rheumatology AOUC, University of Florence, Florence, ItalyDepartment of Translational Medical Sciences, University of Naples Federico II, Naples, ItalyCenter for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Naples, ItalyDepartment of Translational Medical Sciences, University of Naples Federico II, Naples, ItalyCenter for Basic and Clinical Immunology Research (CISI), WAO Center of Excellence, University of Naples Federico II, Naples, ItalySystemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis, alteration in the microvasculature and immunologic abnormalities. It has been hypothesized that an abnormal redox state could regulate the persistent fibrotic phenotype in SSc patients. N-Formyl peptide receptors (FPRs) are chemotactic receptors overexpressed in fibroblasts derived from SSc patients. In this study, we demonstrated that stimulation of FPRs promotes the generation of reactive oxygen species (ROS) in skin fibroblasts. In fibroblast cells, ROS production was due to FPRs interaction with the urokinase receptor (uPAR) and to β1 integrin engagement. FPRs cross-talk with uPAR and integrins led to Rac1 and ERKs activation. FPRs stimulation increased gp91phox and p67phox expression as well as the direct interaction between GTP-Rac1 and p67phox, thus promoting assembly and activation of the NADPH oxidase complex. FPRs functions occur through interaction with a specific domain of uPAR (residues 88SRSRY92) that can be exposed on the cell membrane by protease-mediated receptor cleavage. Immunohistochemistry analysis with a specific anti-SRSRY antibody showed increased expression of uPAR in a cleaved form, which exposes the SRSRY sequence at its N-terminus (DIIDIII-uPAR88–92) in skin biopsies from SSc patients. As expected by the increased expression of both FPRs and DII-DIII-uPAR88-92, fibroblasts derived from SSc patients showed a significantly increase in ROS generation both at a basal level than after FPRs stimulation, as compared to fibroblasts from normal subjects. C37, a small molecule blocking the interaction between FPRs and uPAR, and selumetinib, a clinically approved MAPKK/ERK inhibitor, significantly inhibited FPRs-mediated ROS production in fibroblasts derived from SSc patients. Thus, FPRs, through the interaction with the uPA/uPAR system, can induce ROS generation in fibroblasts by activating the NADPH oxidase, playing a role in the alteration of the redox state observed in SSc.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00574/fullinflammationfibrosissystemic sclerosisFPRsuPARintegrin |
| spellingShingle | Filomena Napolitano Francesca Wanda Rossi Francesca Wanda Rossi Ada Pesapane Silvia Varricchio Gennaro Ilardi Massimo Mascolo Stefania Staibano Antonio Lavecchia Pia Ragno Carmine Selleri Gianni Marone Gianni Marone Gianni Marone Marco Matucci-Cerinic Marco Matucci-Cerinic Amato de Paulis Amato de Paulis Nunzia Montuori Nunzia Montuori N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor Frontiers in Immunology inflammation fibrosis systemic sclerosis FPRs uPAR integrin |
| title | N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor |
| title_full | N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor |
| title_fullStr | N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor |
| title_full_unstemmed | N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor |
| title_short | N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor |
| title_sort | n formyl peptide receptors induce radical oxygen production in fibroblasts derived from systemic sclerosis by interacting with a cleaved form of urokinase receptor |
| topic | inflammation fibrosis systemic sclerosis FPRs uPAR integrin |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00574/full |
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