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N-Formyl Peptide Receptors Induce Radical Oxygen Production in Fibroblasts Derived From Systemic Sclerosis by Interacting With a Cleaved Form of Urokinase Receptor
- Source :
- Frontiers in Immunology, Frontiers in Immunology, Vol 9 (2018)
- Publication Year :
- 2018
- Publisher :
- Frontiers Media S.A., 2018.
-
Abstract
- 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.
- Subjects :
- lcsh:Immunologic diseases. Allergy
0301 basic medicine
MAPK/ERK pathway
Fibrosi
systemic sclerosis
integrin
Integrin
Immunology
FPRs
RAC1
03 medical and health sciences
Systemic sclerosi
0302 clinical medicine
fibroblasts
medicine
Immunology and Allergy
Receptor
Fibroblast
skin and connective tissue diseases
Original Research
NADPH oxidase
biology
Chemistry
fibrosis
Chemotaxis
ROS
Cell biology
Urokinase receptor
Fibroblasts
Fibrosis
Inflammation
Systemic sclerosis
UPAR
030104 developmental biology
medicine.anatomical_structure
inflammation
030220 oncology & carcinogenesis
biology.protein
FPR
lcsh:RC581-607
uPAR
Subjects
Details
- Language :
- English
- ISSN :
- 16643224
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Frontiers in Immunology
- Accession number :
- edsair.doi.dedup.....c6394be29d524869bbe28baffbf325da