Upregulation of the N-formyl Peptide receptors in scleroderma fibroblasts fosters the switch to myofibroblasts.

Abstract

Systemic sclerosis (SSc) is characterized by chronic inflammation and fibrosis. N-Formyl peptide (fMLF) receptors (FPRs) are chemotactic receptors involved in inflammation. Three FPRs have been identified: FPR1, FPR2, and FPR3. We have examined, by RT-PCR, Western blot and immunohistochemistry, FPRs expression in skin fibroblasts from 10 normal subjects and 10 SSc patients, showing increased expression in SSc fibroblasts. Several functions of FPRs occur through the interaction with a region of the urokinase-type plasminogen activator receptor (uPAR88-92), able to interact with FPRs and to mediate urokinase (uPA) or fMLF-dependent cell migration. Soluble uPAR84-95 peptide can act as a direct ligand of FPRs. Furthermore, uPA or its aminoterminal fragment (ATF) can promote the exposure of the uPAR88-92 region. The WKYMVm peptide is a FPRs pan-agonist. We investigated the functional effects of these agonists on normal and SSc fibroblasts. ATF, uPAR84-95, and WKYMVm regulated adhesion, migration, and proliferation of normal fibroblasts. Despite FPR overexpression, the response of SSc fibroblasts to the same agonists was greatly reduced, except for the proliferative response to ATF. SSc fibroblasts showed increased α-smooth muscle actin expression and improved capability to induce wound closure. Indeed, they overexpressed a cleaved uPAR form, exposing the uPAR88-92 region, and vitronectin, both involved in fibrosis and in the fibroblast-to-myofibroblast transition. FPR stimulation promoted α-smooth muscle actin expression in normal fibroblasts as well as motility, matrix deposition, αvβ5 integrin expression, and radical oxygen species generation in normal and SSc fibroblasts. This study provides evidence that FPRs may play a role in fibrosis and in the fibroblast-to-myofibroblast transition.

• Authors: Francesca Wanda Rossi, Filomena Napolitano, Ada Pesapane, Massimo Mascolo, Stefania Staibano, Marco Matucci-Cerinic, Serena Guiducci, Pia Ragno, Gaetano di Spigna, Loredana Postiglione, Gianni Marone, Nunzia Montuori, Amato de Paulis
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 194 Issue 11 Pg. 5161-73 (Jun 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 25917089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Actins
• FPR1 protein, human
• FPR2 protein, human
• FPR3 protein, human
• Oligopeptides
• Peptide Fragments
• Reactive Oxygen Species
• Receptors, Formyl Peptide
• Receptors, Lipoxin
• Receptors, Urokinase Plasminogen Activator
• Receptors, Vitronectin
• Trp-Lys-Tyr-Met-Val-Met
• Vitronectin
• integrin alphaVbeta5
• Urokinase-Type Plasminogen Activator

Topics

• Actins (biosynthesis)
• Adult
• Aged
• Cell Adhesion (drug effects)
• Cell Differentiation
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Female
• Fibrosis (immunology, pathology)
• Humans
• Inflammation (immunology)
• Male
• Middle Aged
• Myofibroblasts (cytology, metabolism)
• Oligopeptides (pharmacology)
• Peptide Fragments (pharmacology)
• Reactive Oxygen Species (metabolism)
• Receptors, Formyl Peptide (biosynthesis, metabolism)
• Receptors, Lipoxin (biosynthesis, metabolism)
• Receptors, Urokinase Plasminogen Activator (genetics, metabolism)
• Receptors, Vitronectin (biosynthesis)
• Scleroderma, Systemic (immunology, pathology)
• Skin (metabolism)
• Transcriptional Activation
• Urokinase-Type Plasminogen Activator (metabolism)
• Vitronectin
• Wound Healing (physiology)