Upregulation of the N -Formyl Peptide Receptors in Scleroderma Fibroblasts Fosters the Switch to Myofibroblasts

• Published in: The Journal of immunology (1950) Vol. 194; no. 11; pp. 5161 - 5173
• Main Authors: Rossi, Francesca Wanda, Napolitano, Filomena, Pesapane, Ada, Mascolo, Massimo, Staibano, Stefania, Matucci-Cerinic, Marco, Guiducci, Serena, Ragno, Pia, di Spigna, Gaetano, Postiglione, Loredana, Marone, Gianni, Montuori, Nunzia, de Paulis, Amato
• Format: Journal Article
• Language: English
• Published: United States 01.06.2015
• Subjects: Actins - biosynthesis; Adult; Aged; Cell Adhesion - drug effects; Cell Differentiation; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Female; Fibrosis - immunology; Fibrosis - pathology; Humans; Inflammation - immunology; Male; Middle Aged; Myofibroblasts - cytology; Myofibroblasts - metabolism; Oligopeptides - pharmacology; Peptide Fragments - pharmacology; Reactive Oxygen Species - metabolism; Receptors, Formyl Peptide - biosynthesis; Receptors, Formyl Peptide - metabolism; Receptors, Lipoxin - biosynthesis; Receptors, Lipoxin - metabolism; Receptors, Urokinase Plasminogen Activator - genetics; Receptors, Urokinase Plasminogen Activator - metabolism; Receptors, Vitronectin - biosynthesis; Scleroderma, Systemic - immunology; Scleroderma, Systemic - pathology; Skin - metabolism; Transcriptional Activation; Urokinase-Type Plasminogen Activator - metabolism; Vitronectin; Wound Healing - physiology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1402819

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.