The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression

Abstract

Fibrotic diseases, such as systemic sclerosis (SSc), idiopathic pulmonary fibrosis, renal fibrosis and liver cirrhosis are characterized by tissue overgrowth due to excessive extracellular matrix (ECM) deposition. Fibrosis progression is caused by ECM overproduction and the inhibition of ECM degradation due to several events, including inflammation, vascular endothelial dysfunction, and immune abnormalities. Recently, it has been reported that urokinase plasminogen activator (uPA) and its receptor (uPAR), known to be fibrinolytic factors, orchestrate the inflammatory response, vascular homeostasis, and immune homeostasis system. The uPA/uPAR system may show promise as a potential therapeutic target for fibrotic diseases. This review considers the role of the uPA/uPAR system in the progression of fibrotic diseases.

The Roles of Fibrinolytic Factors in Bone Destruction Caused by Inflammation

“…The interaction between uPA and uPAR may play a role in mediating inflammatory osteoclast formation and bone loss through multiple mechanisms, including plasmin-dependent and -independent cell signaling. On the other hand, uPAR can interact with several factors, including integrins, VEGFR2, and caveolin-1 [ 8 ]. The binding of connective tissue growth factor (CTGF) to integrin αvβ3 induces osteocyte apoptosis through the activation of ERK1/2 [ 108 ].…”

“…In recent years, numerous studies have demonstrated that these fibrinolytic factors not only degrade fibrin but also serve various functions, including growth factor activation, cytokine production, cell differentiation, cell proliferation, and cell migration. They play pivotal roles in biological processes such as inflammation, tissue remodeling, angiogenesis, and the immune system [ 6 , 7 , 8 , 9 ]. Fibrinolytic factors are expressed in bone cells including osteoclasts, osteoblasts, and osteocytes and are considered essential in maintaining bone homeostasis by regulating the functions of osteoclasts, osteoblasts, and osteocytes [ 10 ].…”

The Crosstalk between N-Formyl Peptide Receptors and uPAR in Systemic Sclerosis: Molecular Mechanisms, Pathogenetic Role and Therapeutic Opportunities

“…Many functions of FPRs occur through their interaction with the urokinase-type plasminogen activator receptor (uPAR) [ 21 , 22 , 23 ]. uPAR, a glycosyl-phosphatidyl-inositol-(GPI)-anchored protein formed by three domains (DI-DII-DIII), serves to bind the urokinase plasminogen activator (uPA) and localize the reactions of the plasminogen activation system on the cell membrane [ 24 , 25 , 26 , 27 ]. After removal of the GPI anchor by proteases or phospholipases, uPAR sheds from the cell membrane and exists as a soluble form (suPAR) that is detectable in various body fluids [ 28 ].…”

Tissue-plasminogen activator effects on the phenotype of splenic myeloid cells in acute inflammation

“…Important bidirectional interactions exist between hemostasis and inflammation, two biological systems that are phylogenetically linked as host defence mechanisms [ 14 – 16 ]. Plasminogen (PLG)/plasmin system regulates the fibrinolysis and extracellular matrix degradation but also has diverse functions in inflammation [ 17 – 19 ]. This system comprises serine proteases, tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) that cleave the PLG zymogen into plasmin, a key downstream enzyme that degrades fibrin.…”

“…Beside their critical function in the fibrinolytic system, many reports indicate that tPA and uPA have also a complex role in inflammation and innate immunity [ 19 – 22 ]. Contrasting effects of PLG activators depend on their proteolytic activity or are mediated by a “cytokine-like” mode through interactions with specific receptors [ 23 ].…”