Upregulation of the N-formyl Peptide receptors in scleroderma fibroblasts fosters the switch to myofibroblasts.
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.
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy;
Francesca Wanda
FW
Rossi
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy;
Filomena
F
Napolitano
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy;
Ada
A
Pesapane
Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy;
Massimo
M
Mascolo
Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy;
Stefania
S
Staibano
Department of Biomedicine, University of Florence, 50121 Florence, Italy; and.
Marco
M
Matucci-Cerinic
Department of Biomedicine, University of Florence, 50121 Florence, Italy; and.
Serena
S
Guiducci
Department of Chemistry and Biology, University of Salerno, 84084 Salerno, Italy.
Pia
P
Ragno
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy;
Gaetano
G
di Spigna
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy;
Loredana
L
Postiglione
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy;
Gianni
G
Marone
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy; nmontuor@unina.it.
Nunzia
N
Montuori
Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research, University of Naples Federico II, 80131 Naples, Italy;
Amato
A
de Paulis
D000199:Actins / Q000096:biosynthesis; D000328:Adult; D000368:Aged; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005355:Fibrosis / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000096:biosynthesis / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000096:biosynthesis; D012595:Scleroderma, Systemic / Q000276:immunology / Q000473:pathology*; D012867:Skin / Q000378:metabolism; D015533:Transcriptional Activation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D019096:Vitronectin; D014945:Wound Healing / Q000502:physiology
D000199:Actins; C469986:FPR1 protein, human; C105101:FPR2 protein, human; C469985:FPR3 protein, human; D009842:Oligopeptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin; C113617:Trp-Lys-Tyr-Met-Val-Met; D019096:Vitronectin; C064660:integrin alphaVbeta5; D014568:Urokinase-Type Plasminogen Activator