Journal
FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.845956
Keywords
skin fibrosis; scleroderma; uPA system; systemic sclerosis; fibroblast
Categories
Funding
- Natural Science Foundation of China [81770876]
- Natural Science Foundation of Jiangsu Province [BK20191141]
- Top Talent Support Program for young and middle-aged people of Wuxi Health Committee
- Fundamental Research Funds of Health and Family Planning Commission of Wuxi [M202024]
- [BJ2020044: BJ2020057]
- [HB2020043]
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Skin fibrosis is a common pathological feature of various diseases. The urokinase-type plasminogen activator (uPA) system, including uPA, urokinase plasminogen activator receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1), is upregulated in fibrotic diseases. The successful binding of uPA and uPAR activates the downstream peroxisome proliferator-activated receptor (PPAR) signaling pathway, reducing the proliferation, migration, and contraction of disease-derived fibroblasts and alleviating skin fibrosis. However, increased or robust upregulation of PAI-1 inhibits these effects, suggesting the involvement of PAI-1 in skin fibrosis.
Skin fibrosis is a common pathological feature of various diseases, and few treatment strategies are available because of the molecular pathogenesis is poorly understood. The urokinase-type plasminogen activator (uPA) system is the major serine protease system, and its components uPA, urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1(PAI-1) are widely upregulated in fibrotic diseases, including hypertrophic scars, keloids, and scleroderma. Here, we found that the successful binding of uPA and uPAR activates the downstream peroxisome proliferator-activated receptor (PPAR) signalling pathway to reduce the proliferation, migration, and contraction of disease-derived fibroblasts, contributing to the alleviation of skin fibrosis. However, increased or robust upregulation of the inhibitor PAI-1 inhibits these effects, suggesting of the involvement of PAI-1 in skin fibrosis. Subsequent in vivo studies showed that uPAR inhibitors increased skin fibrosis in mouse models, while uPA agonists and PAI-1 inhibitors reversed these effects. Our findings demonstrate a novel role for the uPA system and highlights its relationships with skin fibrosis, thereby suggesting new therapeutic approaches targeting the uPA system.
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