Next Article in Journal
MicroRNAs Associated with Chronic Kidney Disease in the General Population and High-Risk Subgroups—A Systematic Review
Previous Article in Journal
Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 24
Issue 2
10.3390/ijms24021796
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

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

by
Yosuke Kanno
Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women’s College of Liberal Arts, Kyoto 610-0395, Japan
Int. J. Mol. Sci. 2023, 24(2), 1796; https://doi.org/10.3390/ijms24021796
Submission received: 6 December 2022 / Revised: 11 January 2023 / Accepted: 13 January 2023 / Published: 16 January 2023
(This article belongs to the Section Molecular Biology)
Browse Figures
Versions Notes

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.
Keywords:
uPA; uPAR; plasmin; fibrosis 23

1. Introduction

Fibrosis is characterized by the deposition of excessive extracellular matrix (ECM) components, such as collagen and fibronectin. Fibrosis is a prominent pathological feature of chronic autoimmune diseases (systemic sclerosis [SSc], systemic lupus erythematosus [SLE], rheumatoid arthritis, ulcerative colitis, Crohn’s disease, myelofibrosis) and chronic kidney disease (CKD; diabetes mellitus, hypertension, infection, glomerulonephritis), and causes organ dysfunction or death [1,2]. The common feature of all fibrotic diseases is the deposition and activation of myofibroblasts, which causes excessive ECM production [3]. Myofibroblast deposition is induced by the differentiation of tissue-resident fibroblast and bone marrow-derived mesenchymal stem cells (MSCs), epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndoMT), and macrophage-to-myofibroblast transition (MMT) [4,5,6,7,8,9]. In contrast, matrix metalloproteinases (MMPs) and plasmin contribute to ECM degradation [10,11], and MMPs are also associated with fibrosis progression [12,13,14,15,16,17]. Tissue inhibitor of MMPs (TIMP) and plasmin inhibitor (α2-antiplasmin [α2AP]) expression is elevated in fibrotic tissues [18,19,20,21,22,23]. Inhibitors of MMPs, plasmin, and urokinase plasminogen activator (uPA) (TIMP, α2AP, and plasminogen activator inhibitor-1 [PAI-1], respectively) cause impaired ECM degradation. Together, ECM overproduction and its impaired degradation induce fibrosis progression. Vascular dysfunction (endothelial cell [EC] damage, defective angiogenesis, and coagulation abnormalities) and abnormalities in the immune system (immune activation, T-cells, B-cells, macrophages infiltration, and autoantibodies production) affect ECM deposition and fibrosis progression (Figure 1) [1,11,24].
uPA and its receptor (uPAR) convert plasminogen (Plg) into plasmin [25]. Plasmin regulates fibrinolysis, the activation of growth factors, activation of MMPs, ECM degradation, hormone processing, and activation of factor V, factor VIII, factor X, and protease-activated receptors (PARs). Plasmin is associated with multiple cell functions, cytokine production, apoptosis, and tissue remodeling, as well as inflammation through various mechanisms (Figure 2) [11,26,27,28,29,30,31]. In contrast, uPA and uPAR interact with transmembrane proteins, such as integrins, and regulate cell growth, migration, differentiation, and adhesion [32,33,34,35,36]. uPA and uPAR mediate inflammation and the immune response, tissue remodeling, and angiogenesis, and are involved in the progression of fibrotic diseases, such as SSc and rheumatoid arthritis [32,34,37,38,39]. This review describes the roles of uPA and uPAR in the pathogenesis of fibrotic diseases.

2. The uPA and uPAR System

The uPA and uPAR system can convert Plg into plasmin or activate intercellular signaling and regulates fibrinolysis, cell proliferation, migration, differentiation, and adhesion. The uPA/uPAR system is associated with the immune response, angiogenesis, inflammation, tissue remodeling, bone metabolism, glucose metabolism, and fibrosis progression [13,36,37,40,41,42,43,44].

2.1. uPA

uPA is a single-chain serine protease that can cleave and activate Plg into plasmin by binding to uPAR [45]. uPA is secreted as a single-chain glycosylated zymogen called pro-uPA, and pro-uPA is activated by several proteinases, such as kallikrein, stromelysin, and plasmin [45]. uPA consists of three domains: an N-terminal epidermal growth factor (EGF)-like domain (which together with the N-terminal domain form the amino-terminal fragment [ATF]), and catalytic serine protease domain [46,47]. uPA is expressed in many types of cells, including leukocytes, macrophages, tumor cells, and fibroblasts [40]. uPA can bind to the uPAR D1 domain through its EGF-like domain [47]. The uPA/uPAR interaction mediates various signal pathways, such as phosphatidylinositol 3-kinase (PI3K)/Akt, AMP-activated protein kinase (AMPK), extracellular-signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) [27,34,48]. PAI-1 blocks uPA and inhibits plasmin production and the fibrinolytic system [49].

2.2. uPAR

uPAR is a glycosyl-phosphatidyl-inositol anchored (GPI) membrane protein that consists of three domains: D1 (residues 1–92), D2 (residues 93–191) and D3 (residues 192–283) [50]. uPAR is cleaved between the D1 and D2 domains (linker region) and the GPI-anchor domain by several proteases, such as uPA, plasmin, MMPs, and GPI-specific phospholipase D, and then forms soluble uPAR (suPAR; full length D1-D3, D2D3, and D1) (Figure 3) [51]. uPAR can interact with various transmembrane receptors, including integrins, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and insulin-like growth factor 1 receptor (IGF1R), as well as regulate signal transduction [32,50]. In addition, uPAR can interact with low-density lipoprotein receptor (LRP), and this uPAR/LRP interaction is associated with uPAR recycling [52]. uPAR can also bind to vitronectin, and the vitronectin/uPA/suPAR complex leads to increased PA activity [53]. Furthermore, suPAR can activate formyl peptide receptor (FPR) [54]. The functions of uPAR regulate various signaling pathways, such as PI3K/Akt, focal adhesion kinase (FAK), and Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT), and is associated with the immune response, angiogenesis, inflammation, and fibrosis (Figure 4). uPAR is expressed on a variety of cells, including fibroblasts, monocytes, macrophages, keratinocytes, neurons, ECs and smooth muscle cells [27], and uPAR expression is induced by inflammation [33,55]. It has been reported that increased uPAR expression is observed in many fibrosis-related diseases, including cardiac fibrosis, idiopathic pulmonary fibrosis, and SSc (Figure 5) [56,57,58,59,60,61,62,63].

3. The Role of the uPA/uPAR System in Fibrosis

Fibrosis is characterized by ECM deposition due to the overproduction of ECM and the inhibition of ECM degradation. Many fibrotic events, such as vascular endothelial dysfunction and immune abnormalities, are associated with the activation and differentiation of myofibroblasts and the inhibition of ECM-depredating proteases, including MMPs and plasmin, which cause ECM deposition [9,11,64,65,66,67].
Induction of uPA activity attenuates pulmonary fibrosis in fibrosis model mice [67]. In addition, transplantation of uPA gene attenuates liver fibrosis in liver fibrosis model rats [68]. uPAR deficiency induces perivascular fibrosis, dermal fibrosis, and pulmonary fibrosis in mice [13,69,70] and accelerates renal fibrosis in obstructive nephropathy model mice [71]. In contrast, suPAR is elevated in focal segmental glomerulosclerosis (FSGS) [72], and uPAR deficiency attenuates LPS-induced glomerulosclerosis [73]. uPAR isoform 2 transgenic mice exhibit glomerulosclerosis and kidney dysfunction [74]. In addition, UPARANT (Ac-L-Arg-Aib-L-Arg-D-Cα(Me)Phe-NH2), which blocks uPAR binding to the FPR, restores STZ-induced renal fibrosis [75]; therefore, uPAR affects renal fibrosis progression.
Plasmin not only degrades fibrin but also induces MMP and PAR activity. Fibrin and PAR activation promotes fibrosis, and MMPs play an important role in ECM degradation [76,77]. In addition, plasmin-induced hepatocyte growth factor (HGF) activation and vascular endothelial growth factor (VEGF) release may affect fibrosis progression [78,79]. Furthermore, α2AP and PAI-1 deficiency attenuated fibrosis progression in fibrosis model mice [21,78,80,81,82]. These data suggest that the uPA/uPAR system plays a pivotal role in the progression of fibrosis through multiple plasmin-dependent and plasmin-independent mechanisms.

3.1. Myofibroblasts in Fibrosis

Myofibroblasts contribute to excessive ECM production and play a pivotal role in fibrotic disorders [3,66]. It has been reported that various cell types, including fibroblasts, pericytes, bone-marrow-derived fibrocytes, tissue-derived MSCs, ECs, epithelial cells, and macrophages give rise to myofibroblasts [83]. Inflammation or mechanical stresses induce pro-fibrotic factors, including transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), and interleukins (ILs). Myofibroblasts are raised from MSCs, pericytes and pre-adipocytes, epithelial cells, ECs, and macrophages through differentiation, EMT, EndoMT, or MMT induced by pro-fibrotic factors [3,5,84,85,86,87,88,89]. Furthermore, the apoptosis resistance of myofibroblasts has been observed in several fibrotic tissues [66]. TGF-β and PDGF inhibit myofibroblast apoptosis [66,90,91]. In contrast, HGF induces myofibroblast apoptosis through FAK-ERK signaling, and suppresses fibrosis progression [92,93]. The evasion of apoptosis in myofibroblasts may play a pivotal role in the progression of fibrosis.

3.1.1. The uPA/uPAR System and Myofibroblasts

Plasmin induces myofibroblast differentiation through glycogen synthase kinase-3β (GSK-3β) signaling [94]. In contrast, plasmin induces apoptosis of myofibroblasts [95]. Plasmin plays an important role in myofibroblast deposition in fibrosis. uPA overexpression attenuates myofibroblast differentiation in SSc fibroblasts [96], and uPA deficiency enhances myofibroblast differentiation through Endo180 and uPAR [97]. Furthermore, the induction of uPA activity in mice increases myofibroblast apoptosis [67]. In contrast, treatment with uPA increases myofibroblast differentiation [98], and the knockdown and inhibition of uPA attenuate TGF-β-induced myofibroblast differentiation [99]. uPAR deficiency in mice also increases myofibroblasts [13], and the blockade of uPAR cleavage by protease inhibitors prevents myofibroblast differentiation [100]. uPAR deficiency and silencing cause EndoMT and EMT [101,102]. In contrast, uPAR silencing by siRNA attenuates EGF-, TGF-β-, the cigarette smoke extract (CSE)-, and hypoxia-induced EMT [103,104,105,106]. The uPA/uPAR system regulates myofibroblast differentiation through multiple plasmin-dependent and plasmin-independent mechanisms.

3.1.2. uPAR-Binding Protein and Myofibroblasts

uPAR can interact with several factors, including integrins, EGFR, PDGFR, VEGFR2, caveolin-1, and LRP [50].
The blockade of integrin αvβ3 by RGD peptide and the knockdown of integrin αv and β1 inhibits myofibroblast differentiation [107,108]. In addition, RGD peptide reverts EndoMT [109], and integrin α3 knockout prevents TGF-β-induced EMT [110]. In contrast, integrin α5 silencing promotes myofibroblast differentiation [111]. EGFR activation promotes an increase in myofibroblasts [112]. EGF neutralization inhibits myofibroblast proliferation [113], and the inhibition of EGFR signaling blocks EMT and EndoMT [114,115]. The inhibition of PDGFR promotes a reduction in myofibroblasts [116] and interferes with EMT [117]. In addition, neutralization of TGF-β and PDGFR signaling abolishes platelet-induced EndoMT [118]. VEGF-VEGFR2 signaling promotes EMT [119], and VEGFR2 inhibitor reverses TGF-β-induced EMT [120]. In contrast, VEGFR2 antagonism induces EndoMT [121]. The downregulation of caveolin is associated with anti-apoptotic properties of myofibroblasts [122]. Overexpression of caveolin-1 inhibits EMT [123], and the disappearance of caveolin-1 causes EMT and EndoMT [124,125]. The loss of LRP-1 promotes myofibroblast differentiation [126].
These uPAR-associated factors regulate the activation and differentiation of myofibroblasts, suggesting that the interaction with uPAR may play an important role in myofibroblast differentiation.

3.1.3. Other Fibrinolytic Factors and Myofibroblasts

The uPA/uPAR system, as well as other fibrinolytic factors, such as tPA, PAI-1 and α2AP are associated with myofibroblast activation and differentiation.
tPA is a Plg activator that also converts Plg into plasmin. tPA deficiency increases apoptosis of interstitial myofibroblasts in a mouse model of obstructive injury, and tPA is associated with myofibroblast apoptosis [127]. In addition, tPA induces myofibroblast activation through LRP-1 activation [128].
PAI-1 regulates plasmin production by inhibiting tPA and uPA. PAI-1-specific inhibitor attenuates TGF-β-mediated myofibroblast differentiation and EMT [129]. The knockdown of PAI-1 by siRNA and PAI-1 inhibition decreases myofibroblasts [130,131]. TGF-β is known to induce PAI-1 expression and inhibit uPA, and uPA binding to PAI-1 induces myofibroblast differentiation [98]. Increases in the PAI-1 expression may promote fibrosis progression. However, it has been reported that PAI-1 deficiency increases myofibroblasts, and PAI-1 deficient ECs are more susceptible to TGF-β-induced EndoMT than wild-type ECs [132,133,134]. Elevated PAI-1 expression reportedly decreases myofibroblasts [135].
α2AP rapidly inactivates plasmin by inducing the formation of plasmin–α2AP complex. In contrast, α2AP deficiency attenuates dermal fibrosis in mice [80]. In addition, α2AP promotes myofibroblast differentiation and fibrosis through ATGL activation [136], and the blockade of α2AP by neutralizing antibodies or miRNA attenuates myofibroblast differentiation and fibrosis [22,137]. Furthermore, α2AP is associated with the induction of EMT and EndoMT [21,138]. α2AP may also regulate myofibroblast activation and differentiation through multiple functions.

3.2. Suppression of ECM Depredating Protease in Fibrosis

The suppression of ECM degradation, as well as the overproduction of ECM, causes the progression of fibrosis [10]. Proteases, including MMPs, plasmin, and uPA, regulate ECM degradation, and the activity of these proteases is inhibited by TIMPs, α2AP, and PAI-1, respectively. An imbalance between proteases and anti-proteases may promote fibrosis progression.
MMPs can be divided into six classes: collagenases, including MMP-1, MMP-8, and MMP-13; gelatinases, including MMP-2 and MMP-9; stromelysins, including MMP-3, MMP-10, and MMP-11; matrilysins, including MMP-7 and MMP-26; membrane-type MMPs, including MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, and MMP-25; and others [139]. MMPs degrade ECM components, including collagen, fibronectin, laminin, entactin, tenascin, thrombospondin, and perlecan, and maintain ECM homeostasis. MMP-3 induces inactivation of α2AP and PAI-1 [19,140]. Several proteinases, including plasmin and uPA, induce the activation of MMPs. Plasmin activates MMP-1, MMP-3, MMP-9, MMP-10, and MMP-13, and uPA activates MMP-2 and MMP-9 in a plasmin-independent manner [140]. In contrast, uPAR deficiency attenuates MMP-2 and MMP-9 expression and activation [13]. Thus, the uPA/uPAR system affects MMP expression and activation.
TIMPs (TIMP-1-4) are important inhibitors of MMPs [18]. TIMPs are secreted by various cells, including immune cells, fibroblasts, and hepatocytes, and tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) induce TIMP expression [10,18,141,142]. TIMP-1 and TIMP-2 levels are elevated in several types of fibrosis, including SSc, pulmonary fibrosis, liver cirrhosis, renal fibrosis, and myocardial fibrosis [14,18,65,143,144,145,146,147,148,149,150]. α2AP is elevated in fibrotic tissue, including skin and renal fibrosis [21,22,151]. Several fibrosis-associated factors, such as connective tissue growth factor (CTGF), high mobility group box 1 (HMGB1), and interferon-γ (IFN-γ) induce α2AP production [20,23,151]. The overexpression of PAI-1 attenuates ECM degradation by inhibiting the Plg activation system [152]. PAI-1 is regulated by various cytokines, such as TGF-β, EGF, and IL-1β [133]. PAI-1 expression is elevated in various types of fibrosis, including skin fibrosis, lung fibrosis, and renal fibrosis [133,153,154]. Increases in the expression of these factors may contribute to fibrosis progression by suppressing ECM degradation.

4. Vascular Endothelial Dysfunction in Fibrosis

Vascular endothelial dysfunction is caused by EC injury, apoptosis, defective angiogenesis and vasculogenesis, EndoMT, and excessive coagulation, leading to perivascular inflammation, tissue hypoxia, oxidative stress induction, myofibroblast accumulation, hypertension, fibrin deposition, and PARs activation [155,156,157].

4.1. The Role of the uPA/uPAR System in EC Functions

Plasmin is known to play an important role on the maintenance of the vascular endothelial function through fibrinolysis, MMP and cytokine activation, and ECM degradation [11,158]. In addition, plasmin regulates fibrin-, MMP-, and cytokine-mediated EC proliferation, migration, and apoptosis [159,160,161]. In contrast, uPA protects ECs from apoptosis [162,163], and promotes EC proliferation [164]. The proteolytically inactive recombinant of uPA inhibits EC migration [165], and uPAR deficiency alters EC functions, including adhesion, migration, proliferation, and capillary tube formation, and decreases angiogenic functions [166]. uPAR antagonist inhibits the motility of ECs [167]. In addition, the uPA/uPAR system cross-talks with integrins and VEGFR2 and mediates EC tube formation [168]. Furthermore, uPAR-integrin interaction regulates EC migration [169], and the uPA/uPAR system is associated with growth factor-induced EC migration [170,171]. The uPA/uPAR system may regulate EC functions through plasmin-dependent or plasmin-independent mechanisms.

4.2. The Role of the uPA/uPAR System in Angiogenesis

uPA regulates plasmin production and plays an important role in angiogenesis [27]. PA regulates the VEGFR1 and VEGFR2 expression by binding to haematopoietically expressed homeobox protein (HHEX) transcription factor and mediates angiogenesis [172]. uPA and uPAR shRNA enhance TIMP-1-mediated soluble VEGFR1 (sVEGFR1) secretion, and inhibit angiogenesis [173]. Plasmin regulates the vascular endothelial function through fibrinolysis, ECM degradation, and activation of growth factors [11]. In addition, plasmin can release pro-angiogenic factor VEGF from ECM and plays an important role in angiogenesis [174]. The deficiency of α2AP promotes angiogenesis through VEGF over-release in the wound-healing process [79], and α2AP causes the impairment of VEGF signaling [175].
Interaction of uPAR with VEGFR2 regulates VEGF signaling and promotes angiogenesis. [176]. Domain 2 of uPAR regulates uPA-mediated angiogenesis through integrin β1 and VEGFR2 [177]. uPAR also regulates factor XII-stimulated angiogenesis through integrin β1 and EGFR [178]. MMP-12 can cleave uPAR and cause the impairment of angiogenesis [179]. The interaction of uPAR with various factors may regulate its intracellular signaling and play an important role in angiogenesis. In contrast, suPAR and its ser-arg-ser-arg-tyr (SRSRY) sequence (uPAR88-92 sequence) induces angiogenesis [180]. uPAR may thus regulate angiogenesis through multiple mechanisms.

4.3. The Role of the uPA/uPAR System in Coagulation

Hypercoagulation involving fibrin formation contributes to fibrosis progression [77]. The uPA/uPAR system plays a pivotal role in fibrin degradation through plasmin production. uPA and plasmin inhibitors, PAI-1 and α2AP, are elevated in several fibrotic tissue types [11], and the increase in the expression of these factors may cause the impairment of fibrinolysis through the direct inhibition of uPA and plasmin. The impairment of fibrinolysis causes fibrosis, and improvement in fibrinolysis restores fibrosis [77]. In addition, fibrin degradation product fragment can potentiate TGF-β-induced myofibroblast formation [181]. An imbalance in coagulation and fibrinolysis may thus play a critical role in fibrosis progression.

4.4. The Role of the uPA/uPAR System in Vascular Tone Alteration and Hypertension

Hypertension causes cardiac fibrosis [182], while fibrosis leads to pulmonary hypertension [183]. The balance between vasoconstrictor and vasodilator mediators, such as nitric oxide (NO), prostacyclin (PGI2), and endothelin-1 (ET-1), regulates vascular tone, and a shift toward vasoconstriction is associated with hypertension progression [184]. The ratio of uPA and PAI-1 is decreased in idiopathic pulmonary fibrosis patients with pulmonary hypertension [185]. uPA deficiency attenuates hypoxia-induced pulmonary arterial hypertension (PAH) progression [186]. uPAR is associated with SSc-associated PAH [187]. NO is a major vasodilation mediator, and is produced by NO synthase (NOS, including endothelial NOS [eNOS] and inducible NOS [iNOS]). uPA induces eNOS activation through LRP [188]. Treatment with UPARANT, which inhibits uPAR binding to the FPR, attenuates iNOS and NO production [189]. In contrast, iNOS and NO downregulate uPAR expression under hypoxic conditions [190]. The uPA/uPAR system may be associated with vasodilation and the onset of hypertension.

5. Immune Abnormalities and Inflammation in Fibrosis

Chronic inflammation leads to excessive tissue repair and triggers fibrosis progression [191]. Various stimuli, such as tissue injury, allergic response, autoimmune conditions, and infection, can cause inflammation and recruit and activate immune cells [192]. Immune cells, including T-cells, B-cells, macrophages, and dendritic cells (DCs), have been observed in fibrotic tissues [191,193]. T-cells (Th1 cells, Th2 cells, Th17 cells, and regulatory T-cells) secrete various cytokines, including IFN-γ, IL-4, IL-6, IL-12, IL-13, IL-17, and IL-22, and regulate B-cell and macrophage activation, macrophage polarization, myofibroblast differentiation, and ECM production [191,194]. B-cells induce autoantibody and cytokine production and affect EC apoptosis and ECM production [191,195]. In addition, B-cell depletion via antibodies against CD20 attenuates fibrosis progression through the suppression of M2 macrophage polarization in mice [196]. Macrophages play a pivotal role in fibrosis progression, and macrophage depletion markedly suppresses fibrosis progression [151]. Macrophages are divided into M1 and M2 macrophages subsets, and M2 macrophages are elevated under conditions of fibrotic disease [197,198]. M2 macrophage polarization is induced by IL-4 and IL-13 [199], and the inhibition of IL-4 and IL-13 signaling by IL-4Rα antibodies suppresses fibrosis progression in mice [151]. The increase in these immune cells induces production of various pro-fibrotic factors and regulates the inflammatory response, vascular homeostasis, myofibroblast differentiation, and ECM production. Abnormality of the innate and adaptive immune system is associated with fibrosis progression.

6. The Role of the uPA/uPAR System in Inflammation and the Immune System

The uPA/uPAR system regulates cell recruitment, migration, and adhesion, and supports the innate and adaptive immune systems through proteolytic and non-proteolytic mechanisms [200]. Plasmin induced by the uPA/uPAR system has both pro- and anti-inflammatory effects and regulates chemotaxis, invasion, phagocytosis, and cytokine production through PAR-1 or Annexin A2 in various cell types, including monocytes, macrophages, and DCs [201,202,203]. In addition, Plg/plasmin regulates macrophage activation, polarization and efferocytosis [204,205]. Furthermore, plasmin can activate complement factors (C3 and C5), factor XII, and MMPs [203]. Plasmin is also associated with the polarization of T cells [206], and mediates the innate and adaptive immune systems.
uPA regulates macrophage chemotaxis, neutrophil activation, and migration through uPAR-dependent or uPAR-independent mechanisms [207]. uPA also mediates the inflammatory response, such as inflammatory cytokine production and suppression of the NF-κB pathway through plasmin activation [34,200]. Furthermore, uPA induces the production of M2 phenotype macrophages [208]. In contrast, uPAR interacts with several receptors, including integrins and LRP, and participates in the initiation of the innate immune response through the induction of cell adhesion and migration [200]. In addition, uPAR regulates toll-like receptor (TLR) 2, 4, and 7 signaling, and affects inflammation (cytokine production, mediation of NF-κB pathway) and immune responses (neutrophil and macrophage activation, macrophage efferocytosis) [38,209,210,211]. The expression and release of suPAR is induced by inflammation and immune activation [212]. The uPAR-derived ser-arg-ser-arg-tyr (SRSRY) peptide (uPAR88-92 sequence) can interact with FPR1 and is associated with chemokine regulation and monocyte migration [212,213]. The uPA/uPAR system also affects T-cell priming and T-cell effector function [200].
This system has multiple functions and contributes to the inflammatory response and innate and adaptive immune responses.

7. Conclusions and Therapeutic Perspectives

The uPA/uPAR system regulates proteolysis and intracellular signal transduction through multiple plasmin-dependent and plasmin-independent mechanisms, and mediates vascular homeostasis, the immune system, and ECM homeostasis. This review has presented the latest findings, showing that the uPA/uPAR system plays an important role in fibrosis progression. uPA and uPAR are reportedly associated with several pro-fibrotic events, including vascular endothelial dysfunction (EC injury, apoptosis, defective angiogenesis, EndoMT, and excessive coagulation), immune abnormalities (excessive immune activation, immune cells infiltration, and autoantibodies production), and myofibroblast differentiation. In addition, the importance of uPA and uPAR in fibrosis progression has been proven in several animal models. The control of uPA and uPAR expression, uPA/uPAR binding, and uPAR cleavage may improve vascular endothelial dysfunction, immune abnormalities, myofibroblast and ECM deposition, and fibrosis. The regulation of the uPA/uPAR system through several methods, such as neutralizing antibodies, miRNA, peptides, and protease inhibitors, may be a novel therapeutic approach to managing fibrotic diseases. Further investigations will be required to clarify the role of the uPA/uPAR system in fibrotic diseases.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The author declares no conflict of interest.

Abbreviations

α2APα2-antiplasmin
AMPKAMP-activated protein kinase
ATFamino-terminal fragment
CKDchronic kidney disease
CSEcigarette smoke extract
CTGFconnective tissue growth factor
DCdendritic cell
ECMextracellular matrix
EGFepidermal growth factor
EGFRepidermal growth factor receptor
EMTepithelial-to-mesenchymal transition
EndoMTendothelial-to-mesenchymal transition
eNOSendothelial NOS
ET-1endothelin-1
ERKextracellular-signal-regulated kinase
FRPformyl peptide receptor
FSGSfocal segmental glomerulosclerosis
GSK-3βglycogen synthase kinase-3β
HGFhepatocyte growth factor
HMGB1high mobility group box 1
IGF1Rinsulin-like growth factor 1 receptor
IFNinterferon
iNOSinducible NOS
JAKjanus kinase
JNKc-Jun N-terminal kinase
LRPlow-density lipoprotein receptor
MMTmacrophage-to-myofibroblast transition
MMPmatrix metalloproteinase
MSCmesenchymal stem cells
NOnitric oxide
NOSNO synthase
PAHpulmonary arterial hypertension
PAI-1plasminogen activator inhibitor-1
PARprotease-activated receptor
PDGFplatelet-derived growth factor
PDGFRplatelet-derived growth factor receptors
PI3Kphosphatidylinositol 3-kinase
Plgplasminogen
PGE2prostaglandin E2
PGI2prostacyclin
SLEsystemic lupus erythematosus
SScsystemic sclerosis
STATsignal transducer and activator of transcription protein
suPARsoluble uPAR
TGF-βtransforming growth factor-β
TIMPstissue inhibitors of MMPs
TNF-αtumor necrosis factor-α
uPAurokinase plasminogen activator
uPARurokinase plasminogen activator receptor
VEGFvascular endothelial growth factor
VEGFRvascular endothelial growth factor receptor

References

  1. Wynn, T.; Ramalingam, T. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat. Med. 2012, 18, 1028–1040. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Wu, W.; Wang, X.; Yu, X.; Lan, H.-Y. Smad3 Signatures in Renal Inflammation and Fibrosis. Int. J. Biol. Sci. 2022, 18, 2795–2806. [Google Scholar] [CrossRef] [PubMed]
  3. Ortiz-Zapater, E.; Signes-Costa, J.; Montero, P.; Roger, I. Lung Fibrosis and Fibrosis in the Lungs: Is It All about Myofibroblasts? Biomedicines 2022, 10, 1423. [Google Scholar] [CrossRef] [PubMed]
  4. Kanno, Y.; Shu, E. α2-Antiplasmin as a Potential Therapeutic _target for Systemic Sclerosis. Life 2022, 12, 396. [Google Scholar] [CrossRef] [PubMed]
  5. Wei, J.; Xu, Z.; Yan, X. The role of the macrophage-to-myofibroblast transition in renal fibrosis. Front. Immunol. 2022, 13, 934377. [Google Scholar] [CrossRef]
  6. LeBleu, V.S.; Taduri, G.; O’Connell, J.; Teng, Y.; Cooke, V.G.; Woda, C.; Sugimoto, H.; Kalluri, R. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 2013, 19, 1047–1053. [Google Scholar] [CrossRef]
  7. Salton, F.; Ruaro, B.; Confalonieri, P.; Confalonieri, M. Epithelial-Mesenchymal Transition: A Major Pathogenic Driver in Idio-pathic Pulmonary Fibrosis? Medicina 2020, 56, 608. [Google Scholar] [CrossRef]
  8. Confalonieri, P.; Volpe, M.C.; Jacob, J.; Maiocchi, S.; Salton, F.; Ruaro, B.; Confalonieri, M.; Braga, L. Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Cells 2022, 11, 2095. [Google Scholar] [CrossRef]
  9. Egea-Zorrilla, A.; Vera, L.; Saez, B.; Pardo-Saganta, A. Promises and Challenges of Cell-Based Therapies to Promote Lung Re-generation in Idiopathic Pulmonary Fibrosis. Cells 2022, 11, 2595. [Google Scholar] [CrossRef]
  10. Zhao, X.; Chen, J.; Sun, H.; Zhang, Y.; Zou, D. New insights into fibrosis from the ECM degradation perspective: The macro-phage-MMP-ECM interaction. Cell Biosci. 2022, 12, 117. [Google Scholar] [CrossRef]
  11. Kanno, Y. The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis. Int. J. Mol. Sci. 2019, 20, 619. [Google Scholar] [CrossRef] [Green Version]
  12. Chuliá-Peris, L.; Carreres-Rey, C.; Gabasa, M.; Alcaraz, J.; Carretero, J.; Pereda, J. Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play. Int. J. Mol. Sci. 2022, 23, 6894. [Google Scholar] [CrossRef]
  13. Kanno, Y.; Kaneiwa, A.; Minamida, M.; Kanno, M.; Tomogane, K.; Takeuchi, K.; Okada, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. The Absence of uPAR Is Associated with the Progression of Dermal Fibrosis. J. Investig. Dermatol. 2008, 128, 2792–2797. [Google Scholar] [CrossRef] [Green Version]
  14. Waszczykowska, A.; Podgórski, M.; Waszczykowski, M.; Gerlicz-Kowalczuk, Z.; Jurowski, P. Matrix Metalloproteinases MMP-2 and MMP-9, Their Inhibitors TIMP-1 and TIMP-2, Vascular Endothelial Growth Factor and sVEGFR-2 as Predictive Markers of Ischemic Retinopathy in Patients with Systemic Sclerosis-Case Series Report. Int. J. Mol. Sci. 2020, 21, 8703. [Google Scholar] [CrossRef]
  15. Serratì, S.C.M.; Margheri, F.; Guiducci, S.; Del Rosso, A.; Pucci, M.; Fibbi, G.; Bazzichi, L.; Bombardieri, S.; Matucci-Cerinic, M.; Del Rosso, M. Systemic sclerosis fibroblasts inhibit in vitro angiogenesis by MMP-12-dependent cleavage of the endothelial cell uro-kinase receptor. J. Pathol. 2006, 210, 240–248. [Google Scholar] [CrossRef]
  16. Placido, L.; Romero, Y.; Maldonado, M.; Toscano-Marquez, F.; Ramírez, R.; Calyeca, J.; Mora, A.L.; Selman, M.; Pardo, A. Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis. Int. J. Mol. Sci. 2021, 22, 2923. [Google Scholar] [CrossRef]
  17. Kalafatis, D.; Löfdahl, A.; Näsman, P.; Dellgren, G.; Wheelock, M.; Rendin, L.E.; Sköld, M.; Westergren-Thorsson, G. Distal Lung Microenvironment Triggers Release of Mediators Recognized as Potential Systemic Biomarkers for Idiopathic Pulmonary Fibrosis. Int. J. Mol. Sci. 2021, 22, 13421. [Google Scholar] [CrossRef]
  18. Menou, A.; Duitman, J.; Crestani, B. The impaired proteases and anti-proteases balance in Idiopathic Pulmonary Fibrosis. Matrix Biol. 2018, 68-69, 382–403. [Google Scholar] [CrossRef]
  19. Niwa, H.; Kanno, Y.; Shu, E.; Seishima, M. Decrease in matrix metalloproteinase-3 activity in systemic sclerosis fibroblasts causes α2-antiplasmin and extracellular matrix deposition, and contributes to fibrosis development. Mol. Med. Rep. 2020, 22, 3001–3007. [Google Scholar] [CrossRef]
  20. Kanno, Y.; Kawashita, E.; Minamida, M.; Kaneiwa, A.; Okada, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. Alpha2-antiplasmin is associated with the pro-gression of fibrosis. Am. J. Pathol. 2010, 176, 238–245. [Google Scholar] [CrossRef]
  21. Kanno, Y.; Kawashita, E.; Kokado, A.; Kuretake, H.; Ikeda, K.; Okada, K.; Seishima, M.; Ueshima, S.; Matsuo, O.; Matsuno, H. α2AP mediated myofibroblast formation and the development of renal fibrosis in unilateral ureteral obstruction. Sci. Rep. 2014, 4, srep05967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Kanno, Y.; Shu, E.; Kanoh, H.; Seishima, M. The Antifibrotic Effect of α2AP Neutralization in Systemic Sclerosis Dermal Fibroblasts and Mouse Models of Systemic Sclerosis. J. Investig. Dermatol. 2015, 136, 762–769. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Kanno, Y.; Miyashita, M.; Seishima, M.; Matsuo, O. α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses. Immun. Inflamm. Dis. 2020, 8, 267–278. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Kavian, N.; Batteux, F. Macro- and microvascular disease in systemic sclerosis. Vasc. Pharmacol. 2015, 71, 16–23. [Google Scholar] [CrossRef] [PubMed]
  25. Braaten, J.V.; Handt, S.; Jerome, W.G.; Kirkpatrick, J.; Lewis, J.C.; Hantgan, R.R. Regulation of fibrinolysis by platelet-released plasminogen activator inhibitor 1: Light scattering and ultrastructural examination of lysis of a model platelet-fibrin thrombus. Blood 1993, 81, 1290-1299. [Google Scholar] [CrossRef]
  26. Kanno, Y.; Ishisaki, A.; Kawashita, E.; Chosa, N.; Nakajima, K.; Nishihara, T.; Toyoshima, K.; Okada, K.; Ueshima, S.; Matsushita, K. Plasminogen/Plasmin Modulates Bone Metabolism by Regulating the Osteoblast and Osteoclast Function. J. Biol. Chem. 2011, 286, 8952–8960. [Google Scholar] [CrossRef] [Green Version]
  27. Ismail, A.; Shaker, B.; Bajou, K. The Plasminogen-Activator Plasmin System in Physiological and Pathophysiological Angio-genesis. Int. J. Mol. Sci. 2021, 23, 337. [Google Scholar] [CrossRef]
  28. Draxler, D.F.; Sashindranath, M.; Medcalf, R.L. Plasmin: A modulator of immune function. Semin. Thromb. Hemost. 2017, 43, 143–153. [Google Scholar] [CrossRef]
  29. Kanno, Y.; Sakai, A.; Miyashita, M.; Tsuchida, K.; Matsuo, O. Plasminogen deficiency is associated with improved glucose tolerance, and lower DPP-4 activity. Diabetes Res. Clin. Pract. 2016, 120, 190–193. [Google Scholar] [CrossRef]
  30. Law, R.H.; Abu-Ssaydeh, D.; Whisstock, J.C. New insights into the structure and function of the plasminogen/plasmin system. Curr. Opin. Struct. Biol. 2013, 23, 836–841. [Google Scholar] [CrossRef]
  31. Yang, D.; Yang, H.; Luiselli, G.; Ogagan, C.; Dai, H.; Chiu, L.; Carroll, R.S.; Johnson, M.D. Increased plasmin-mediated proteolysis of L1CAM in a mouse model of idiopathic normal pressure hydrocephalus. Proc. Natl. Acad. Sci. USA 2021, 118. [Google Scholar] [CrossRef]
  32. Blasi, F.; Carmeliet, P. uPAR: A versatile signalling orchestrator. Nat. Rev. Mol. Cell Biol. 2002, 3, 932–943. [Google Scholar] [CrossRef]
  33. Smith, H.W.; Marshall, C.J. Regulation of cell signalling by uPAR. Nat. Rev. Mol. Cell Biol. 2010, 11, 23–36. [Google Scholar] [CrossRef]
  34. Kanno, Y.; Ishisaki, A.; Kawashita, E.; Kuretake, H.; Ikeda, K.; Matsuo, O. uPA Attenuated LPS-induced Inflammatory Osteoclas-togenesis through the Plasmin/PAR-1/Ca2+/CaMKK/AMPK Axis. Int. J. Biol. Sci. 2016, 12, 63–71. [Google Scholar] [CrossRef] [Green Version]
  35. Kanno, Y.; Kuroki, A.; Minamida, M.; Kaneiwa, A.; Okada, K.; Tomogane, K.; Takeuchi, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. The absence of uPAR attenuates insulin-induced vascular smooth muscle cell migration and proliferation. Thromb. Res. 2008, 123, 336–341. [Google Scholar] [CrossRef]
  36. Kanno, Y.; Matsuno, H.; Kawashita, E.; Okada, K.; Suga, H.; Ueshima, S.; Matsuo, O. Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue. Thromb. Haemost. 2010, 104, 1124–1132. [Google Scholar] [CrossRef] [Green Version]
  37. Del Rosso, M.; Margheri, F.; Serratì, S.; Chillà, A.; Laurenzana, A.; Fibbi, G. The urokinase receptor system, a key regulator at the intersection between inflammation, immunity, and coagulation. Curr. Pharm. Des. 2011, 17, 1924–1943. [Google Scholar] [CrossRef]
  38. Kanno, Y.; Ishisaki, A.; Miyashita, M.; Matsuo, O. The blocking of uPAR suppresses lipopolysaccharide-induced inflammatory osteoclastogenesis and the resultant bone loss through attenuation of integrin β3/Akt pathway. Immun. Inflamm. Dis. 2016, 4, 338–349. [Google Scholar] [CrossRef]
  39. Kanno, Y.; Maruyama, C.; Matsuda, A.; Ishisaki, A. uPA-derived peptide, Å6 is involved in the suppression of lipopolysaccar-ide-promoted inflammatory osteoclastogenesis and the resultant bone loss. Immun. Inflamm. Dis. 2017, 5, 289–299. [Google Scholar] [CrossRef]
  40. Napolitano, F.; Montuori, N. The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Patho-genesis. J. Clin. Med. 2021, 10, 518. [Google Scholar] [CrossRef]
  41. Mahmood, N.; Mihalcioiu, C.; Rabbani, S.A. Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. Front. Oncol. 2018, 8, 24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Navaratna, D.; Menicucci, G.; Maestas, J.; Srinivasan, R.; McGuire, P.; Das, A. A peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the blood-retinal barrier in diabetes. FASEB J. 2008, 22, 3310–3317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Kalbasi, A.P.; Patecki, M.; Tkachuk, S.; Kiyan, Y.; Haller, H.; Dumler, I. Urokinase receptor mediates osteoclastogenesis via M-CSF release from osteoblasts and the c-Fms/PI3K/Akt/NF-κB pathway in osteoclasts. J. Bone Miner. Res. 2015, 30, 379–388. [Google Scholar]
  44. Tomogane, K.; Kanno, Y.; Kawashita, E.; Okada, K.; Takeuchi, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. The Absence of Urokinase-type Plasminogen Activator Receptor Plays a Role in the Insulin-independent Glucose Metabolism. J. Cardiovasc. Pharmacol. 2011, 57, 334–339. [Google Scholar] [CrossRef] [PubMed]
  45. Masucci, M.T.; Minopoli, M.; Di Carluccio, G.; Motti, M.L.; Carriero, M.V. Therapeutic Strategies _targeting Urokinase and Its Receptor in Cancer. Cancers 2022, 14, 498. [Google Scholar] [CrossRef]
  46. Yepes, M.; Woo, Y.; Martin-Jimenez, C. Plasminogen Activators in Neurovascular and Neurodegenerative Disorders. Int. J. Mol. Sci. 2021, 22, 4380. [Google Scholar] [CrossRef]
  47. Kumar, A.A.; Buckley, B.J.; Ranson, M. The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic _targets. Biomolecules 2022, 12, 152. [Google Scholar] [CrossRef]
  48. Dinesh, P.; Rasool, M. uPA/uPAR signaling in rheumatoid arthritis: Shedding light on its mechanism of action. Pharmacol. Res. 2018, 134, 31–39. [Google Scholar] [CrossRef]
  49. Vaughan, D.E.; Rai, R.; Khan, S.S.; Eren, M.; Ghosh, A.K. Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence. Arter. Thromb. Vasc. Biol. 2017, 37, 1446–1452. [Google Scholar] [CrossRef] [Green Version]
  50. Alfano, D.; Franco, P.; Stoppelli, M.P. Modulation of Cellular Function by the Urokinase Receptor Signalling: A Mechanistic View. Front. Cell Dev. Biol. 2022, 10, 818616. [Google Scholar] [CrossRef]
  51. Enocsson, H.; Sjöwall, C.; Wetterö, J. Soluble urokinase plasminogen activator receptor--a valuable biomarker in systemic lupus erythematosus? Clin. Chim. Acta 2015, 444, 234–241. [Google Scholar] [CrossRef]
  52. Czekay, R.-P.; Kuemmel, T.A.; Orlando, R.A.; Farquhar, M.G. Direct Binding of Occupied Urokinase Receptor (uPAR) to LDL Receptor-related Protein Is Required for Endocytosis of uPAR and Regulation of Cell Surface Urokinase Activity. Mol. Biol. Cell 2001, 12, 1467–1479. [Google Scholar] [CrossRef] [Green Version]
  53. Chavakis, T.; Kanse, S.M.; Yutzy, B.; Lijnen, H.R.; Preissner, K.T. Vitronectin concentrates proteolytic activity on the cell surface and extracellular matrix by trapping soluble urokinase receptor-urokinase complexes. Blood 1998, 91, 2305–2312. [Google Scholar] [CrossRef] [Green Version]
  54. Selleri, C.; Montuori, N.; Ricci, P.; Visconte, V.; Carriero, M.V.; Sidenius, N.; Serio, B.; Blasi, F.; Rotoli, B.; Rossi, G. Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization. Blood 2005, 105, 2198–2205. [Google Scholar] [CrossRef] [Green Version]
  55. Li Santi, A.; Napolitano, F.; Montuori, N.; Ragno, P. The Urokinase Receptor: A Multifunctional Receptor in Cancer Cell Biology. Therapeutic Implications. Int. J. Mol. Sci. 2021, 22, 22084111. [Google Scholar] [CrossRef]
  56. Saxena, A.; Izmirly, P.M.; Han, S.W.; Briassouli, P.; Rivera, T.L.; Zhong, H.; Friedman, D.M.; Clancy, R.M.; Buyon, J.P. Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro-Associated Cardiac Neonatal Lupus. J. Am. Coll. Cardiol. 2015, 66, 930–939. [Google Scholar] [CrossRef] [Green Version]
  57. Akdoğan, J.P.; Yücel, A.A.; Sargin, Z.G.; Sönmez, C.; Yilmaz, G.E.; Özenirler, S. Evaluation of Plasma Urokinase-Type Plasminogen Activator Receptor (UPAR) in Patients with Chronic Hepatitis B, C and Non-Alcoholic Fatty Liver Disease (NAFLD) as Serological Fibrosis Marker. J. Clin. Exp. Hepatol. 2019, 9, 29–33. [Google Scholar] [CrossRef]
  58. Zimmermann, H.W.; Koch, A.; Seidler, S.; Trautwein, C.; Tacke, F. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis. Liver Int. 2012, 32, 500–509. [Google Scholar] [CrossRef]
  59. Xiao, W.; Hsu, Y.-P.; Ishizaka, A.; Kirikae, T.; Moss, R.B. Sputum Cathelicidin, Urokinase Plasminogen Activation System Components, and Cytokines Discriminate Cystic Fibrosis, COPD, and Asthma Inflammation. Chest 2005, 128, 2316–2326. [Google Scholar] [CrossRef] [Green Version]
  60. Desai, B.; Mattson, J.; Paintal, H.; Nathan, M.; Shen, F.; Beaumont, M.; Malinao, M.C.; Li, Y.; Canfield, J.; Basham, B. Differential expression of monocyte/macrophage-selective markers in human idiopathic pulmonary fibrosis. Exp. Lung Res. 2011, 37, 227–238. [Google Scholar] [CrossRef]
  61. Chebotareva, N.; Vinogradov, A.; Cao, V.; Gindis, A.; Berns, A.; Alentov, I.; Sergeeva, N. Serum levels of plasminogen activator urokinase receptor and cardiotrophin-like cytokine factor 1 in patients with nephrotic syndrome. Clin. Nephrol. 2022, 97, 103–110. [Google Scholar] [CrossRef] [PubMed]
  62. Trimarchi, H.; Canzonieri, R.; Schiel, A.; Costales-Collaguazo, C.; Stern, A.; Paulero, M.; Rengel, T.; Andrews, J.; Iotti, A.; Forrester, M. In IgA Nephropathy, Glomerulo-sclerosis Is Associated with Increased Urinary CD80 Excretion and Urokinase-Type Plasminogen Activator Receptor-Positive Podocyturia. Nephron Extra 2017, 7, 52–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Legány, N.; Toldi, G.; Distler, J.H.; Beyer, C.; Szalay, B.; Kovács, L.; Vásárhelyi, B.; Balog, A. Increased plasma soluble urokinase plasminogen activator receptor levels in systemic sclerosis: Possible association with microvascular abnormalities and extent of fibrosis. Clin. Chem. Lab. Med. 2015, 53, 1799–1805. [Google Scholar] [CrossRef] [PubMed]
  64. Gilbane, A.J.; Denton, C.P.; Holmes, A.M. Scleroderma pathogenesis: A pivotal role for fibroblasts as effector cells. Thromb. Haemost. 2013, 15, 215–219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Hasanzadeh, A.; Rafiei, A.; Kazemi, M.; Beiromvand, M.; Bahreini, A.; Khanahmad, H. The Role of Tissue Inhibitor of Metallopro-teinase-1 and 2 in Echinococcus granulosus senso lato-Induced Human Hepatic Fibrosis. Acta Parasitol. 2022, 67, 851–857. [Google Scholar] [CrossRef]
  66. Hinz, B.; Lagares, D. Evasion of apoptosis by myofibroblasts: A hallmark of fibrotic diseases. Nat. Rev. Rheumatol. 2019, 16, 11–31. [Google Scholar] [CrossRef]
  67. Horowitz, J.C.; Tschumperlin, D.J.; Kim, K.K.; Osterholzer, J.J.; Subbotina, N.; Ajayi, I.O.; Teitz-Tennenbaum, S.; Virk, A.; Dotson, M.; Liu, F. Urokinase Plasminogen Activator Overex-pression Reverses Established Lung Fibrosis. Thromb Haemost. 2019, 119, 1968–1980. [Google Scholar]
  68. Sun, C.; Li, D.G.; Chen, Y.W.; Chen, Y.W.; Wang, B.C.; Sun, Q.L.; Lu, H.M. Transplantation of urokinase-type plasminogen activator gene-modified bone marrow-derived liver stem cells reduces liver fibrosis in rats. J. Gene Med. 2008, 10, 855–866. [Google Scholar] [CrossRef]
  69. Dergilev, K.; Beloglazova, I.; Tsokolaeva, Z.; Vasilets, Y.; Parfenova, E. Deficiency of Urokinase-Type Plasminogen Activator Receptor Is Associated with the Development of Perivascular Fibrosis in Mouse Heart. Bull. Exp. Biol. Med. 2022, 173, 5–9. [Google Scholar] [CrossRef]
  70. Manetti, M.; Rosa, I.; Milia, A.F.; Guiducci, S.; Carmeliet, P.; Ibba-Manneschi, L.; Matucci-Cerinic, M. Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: A new model of experimental scleroderma? Ann. Rheum. Dis. 2014, 73, 1700–1709. [Google Scholar] [CrossRef]
  71. Zhang, G.; Kim, H.; Cai, X.; López-Guisa, J.M.; Alpers, C.E.; Liu, Y.; Carmeliet, P.; Eddy, A.A. Urokinase Receptor Deficiency Accelerates Renal Fibrosis in Obstructive Nephropathy. J. Am. Soc. Nephrol. 2003, 14, 1254–1271. [Google Scholar] [CrossRef] [Green Version]
  72. Wei, C.; El Hindi, S.; Li, J.; Fornoni, A.; Goes, N.; Sageshima, J.; Maiguel, D.; Karumanchi, S.A.; Yap, H.K.; Saleem, M. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 2011, 17, 952–960. [Google Scholar] [CrossRef]
  73. Wei, C.; Möller, C.C.; Altintas, M.M.; Li, J.; Schwarz, K.; Zacchigna, S.; Xie, L.; Henger, A.; Schmid, H.; Rastaldi, M.P. Modification of kidney barrier function by the urokinase receptor. Nat. Med. 2007, 14, 55–63. [Google Scholar] [CrossRef] [Green Version]
  74. Wei, C.; Li, J.; Adair, B.D.; Zhu, K.; Cai, J.; Merchant, M.; Samelko, B.; Liao, Z.; Koh, K.H.; Tardi, N.J. uPAR isoform 2 forms a dimer and induces severe kidney disease in mice. J. Clin. Investig. 2019, 129, 1946–1959. [Google Scholar] [CrossRef] [Green Version]
  75. Dal Monte, M.; Cammalleri, M.; Pecci, V.; Carmosino, M.; Procino, G.; Pini, A.; De Rosa, M.; Pavone, V.; Svelto, M.; Bagnoli, P. Inhibiting the urokinase-type plasminogen activator receptor system recovers STZ-induced diabetic nephropathy. J. Cell. Mol. Med. 2019, 23, 1034–1049. [Google Scholar] [CrossRef] [Green Version]
  76. Schuliga, M.; Grainge, C.; Westall, G.; Knight, D. The fibrogenic actions of the coagulant and plasminogen activation systems in pulmonary fibrosis. Int. J. Biochem. Cell Biol. 2018, 97, 108–117. [Google Scholar] [CrossRef]
  77. Oh, H.; Park, H.E.; Song, M.S.; Kim, H.; Baek, J.-H. The Therapeutic Potential of Anticoagulation in Organ Fibrosis. Front. Med. 2022, 9, 866746. [Google Scholar] [CrossRef]
  78. Bauman, K.A.; Wettlaufer, S.H.; Okunishi, K.; Vannella, K.M.; Stoolman, J.S.; Huang, S.K.; Courey, A.J.; White, E.S.; Hogaboam, C.M.; Simon, R.H. The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice. J. Clin. Investig. 2010, 120, 1950–1960. [Google Scholar] [CrossRef] [Green Version]
  79. Kanno, Y.; Hirade, K.; Ishisaki, A.; Nakajima, K.; Suga, H.; Into, T.; Matsushita, K.; Okada, K.; Matsuo, O.; Matsuno, H. Lack of alpha2-antiplasmin improves cutaneous wound healing via over-released vascular endothelial growth factor-induced angiogenesis in wound lesions. J. Thromb. Haemost. 2006, 4, 1602–1610. [Google Scholar] [CrossRef]
  80. Kanno, Y.; Kuroki, A.; Okada, K.; Tomogane, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. alpha2-Antiplasmin is involved in the production of transforming growth factor beta1 and fibrosis. J. Thromb. Haemost. 2007, 5, 2266–2273. [Google Scholar] [CrossRef]
  81. Beier, J.I.; Kaiser, J.P.; Guo, L.; Martínez-Maldonado, M.; Arteel, G.E. Plasminogen activator inhibitor-1 deficient mice are protected from angiotensin II-induced fibrosis. Arch. Biochem. Biophys. 2011, 510, 19–26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Chuang-Tsai, S.; Sisson, T.H.; Hattori, N.; Tsai, C.G.; Subbotina, N.M.; Hanson, K.E.; Simon, R.H. Reduction in Fibrotic Tissue Formation in Mice Genetically Deficient in Plasminogen Activator Inhibitor. Am. J. Pathol. 2003, 163, 445–452. [Google Scholar] [CrossRef] [PubMed]
  83. Tai, Y.; Woods, E.L.; Dally, J.; Kong, D.; Steadman, R.; Moseley, R.; Midgley, A.C. Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis. Biomolecules 2021, 11, 1095. [Google Scholar] [CrossRef] [PubMed]
  84. Platel, V.; Faure, S.; Corre, I.; Clere, N. Endothelial-to-Mesenchymal Transition (EndoMT): Roles in Tumorigenesis, Metastatic Extravasation and Therapy Resistance. J. Oncol. 2019, 2019, 8361945. [Google Scholar] [CrossRef] [PubMed]
  85. Wang, F.; Xia, H.; Yao, S. Regulatory T cells are a double-edged sword in pulmonary fibrosis. Int. Immunopharmacol. 2020, 84, 106443. [Google Scholar] [CrossRef]
  86. Wang, S.; Meng, X.M.; Ng, Y.Y.; Ma, F.Y.; Zhou, S.; Zhang, Y.; Yang, C.; Huang, X.R.; Xiao, J.; Wang, Y.Y. TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis. Onco_target 2015, 7, 8809–8822. [Google Scholar] [CrossRef] [Green Version]
  87. Derada Troletti, C.; Fontijn, R.D.; Gowing, E.; Charabati, M.; van Het Hof, B.; Didouh, I.; van der Pol, S.M.A.; Geerts, D.; Prat, A.; van Horssen, J. Inflammation-induced endothelial to mesenchymal transition promotes brain endothelial cell dysfunction and occurs during multiple sclerosis pathophysiology. Cell Death Dis. 2019, 10, 45. [Google Scholar] [CrossRef] [Green Version]
  88. Wu, N.; Wang, Y.; Wang, K.; Zhong, B.; Liao, Y.; Liang, J.; Jiang, N. Cathepsin K regulates the tumor growth and metastasis by IL-17/CTSK/EMT axis and mediates M2 macrophage polarization in castration-resistant prostate cancer. Cell Death Dis. 2022, 13, 813. [Google Scholar] [CrossRef]
  89. Paquissi, F.; Abensur, H. The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis. Front Med. 2021, 8, 654912. [Google Scholar] [CrossRef]
  90. Zhang, H.; Phan, S. Inhibition of myofibroblast apoptosis by transforming growth factor beta. Am. J. Respir. Cell Mol. Biol. 1999, 21, 658–665. [Google Scholar] [CrossRef]
  91. Tang, W.W.; Ulich, T.R.; Lacey, D.L.; Hill, D.C.; Qi, M.; Kaufman, S.A.; Van, G.Y.; Tarpley, J.E.; Yee, J.S. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am. J. Pathol. 1996, 148, 1169–1180. [Google Scholar]
  92. Iekushi, K.; Taniyama, Y.; Azuma, J.; Sanada, F.; Kusunoki, H.; Yokoi, T.; Koibuchi, N.; Okayama, K.; Rakugi, H.; Morishita, R. Hepatocyte growth factor attenuates renal fibrosis through TGF-β1 suppression by apoptosis of myofibroblasts. J. Hypertens. 2010, 28, 2454–2461. [Google Scholar] [CrossRef]
  93. Yoshimine, H.; Tanoue, S.; Ibi, Y.; Minami, M.; Nakahara, M.; Tokunaga, K.; Kanmura, S.; Ido, A. Hepatocyte growth factor ameliorates methyl-glyoxal-induced peritoneal inflammation and fibrosis in mouse model. Clin. Exp. Nephrol. 2021, 25, 935–943. [Google Scholar] [CrossRef]
  94. Jeffers, A.; Qin, W.; Owens, S.; Koenig, K.B.; Komatsu, S.; Giles, F.J.; Schmitt, D.M.; Idell, S.; Tucker, T.A. Glycogen Synthase Kinase-3β Inhibition with 9-ING-41 At-tenuates the Progression of Pulmonary Fibrosis. Sci. Rep. 2019, 9, 18925. [Google Scholar] [CrossRef] [Green Version]
  95. Kochtebane, N.; Choqueux, C.; Passefort, S.; Nataf, P.; Messika-Zeitoun, D.; Bartagi, A.; Michel, J.B.; Anglés-Cano, E.; Jacob, M.P. Plasmin induces apoptosis of aortic valvular myofibroblasts. J. Pathol. 2009, 221, 37–48. [Google Scholar] [CrossRef]
  96. He, Y.; Tsou, P.; Khanna, D.; Sawalha, A. Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts. Ann. Rheum. Dis. 2018, 77, 1208–1218. [Google Scholar] [CrossRef]
  97. Sugioka, K.; Nishida, T.; Kodama-Takahashi, A.; Murakami, J.; Mano, F.; Okada, K.; Fukuda, M.; Kusaka, S. Urokinase-type plasminogen activator negatively regulates α-smooth muscle actin expression via Endo180 and the uPA receptor in corneal fibroblasts. Am. J. Physiol. Physiol. 2022, 323, C104–C115. [Google Scholar] [CrossRef]
  98. Wang, L.; Ly, C.M.; Ko, C.-Y.; Meyers, E.E.; Lawrence, D.A.; Bernstein, A.M. uPA Binding to PAI-1 Induces Corneal Myofibroblast Differentiation on Vitronectin. Investig. Opthalmology Vis. Sci. 2012, 53, 4765–4775. [Google Scholar] [CrossRef] [Green Version]
  99. Vorstandlechner, V.; Laggner, M.; Copic, D.; Klas, K.; Direder, M.; Chen, Y.; Golabi, B.; Haslik, W.; Radtke, C.; Tschachler, E. The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation. Nat. Commun. 2021, 12, 6242. [Google Scholar] [CrossRef]
  100. Bernstein, A.M.; Twining, S.S.; Warejcka, D.J.; Tall, E.; Masur, S.K. Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation. Mol. Biol. Cell 2007, 18, 2716–2727. [Google Scholar] [CrossRef] [Green Version]
  101. Manetti, M.; Romano, E.; Rosa, I.; Guiducci, S.; Bellando-Randone, S.; De Paulis, A.; Ibba-Manneschi, L.; Matucci-Cerinic, M. Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis. Ann. Rheum. Dis. 2017, 76, 924–934. [Google Scholar] [CrossRef] [PubMed]
  102. Semina, E.V.; Rubina, K.A.; Shmakova, A.A.; Rysenkova, K.D.; Klimovich, P.S.; Aleksanrushkina, N.A.; Sysoeva, V.Y.; Karagyaur, M.N.; Tkachuk, V.A. Downregulation of uPAR promotes urokinase translocation into the nucleus and epithelial to mesenchymal transition in neuroblastoma. J. Cell. Physiol. 2020, 235, 6268–6286. [Google Scholar] [CrossRef] [PubMed]
  103. Wang, P.; Ma, M.; Zhang, S. EGF-induced urokinase plasminogen activator receptor promotes epithelial to mesenchymal tran-sition in human gastric cancer cells. Oncol. Rep. 2017, 38, 2325–2334. [Google Scholar] [CrossRef] [PubMed]
  104. Laurenzana, A.; Biagioni, A.; Bianchini, F.; Peppicelli, S.; Chillà, A.; Margheri, F.; Luciani, C.; Pimpinelli, N.; Del Rosso, M.; Calorini, L. Inhibition of uPAR-TGFβ crosstalk blocks MSC-dependent EMT in melanoma cells. J. Mol. Med. 2015, 93, 783–794. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Wang, Q.; Wang, Y.; Zhang, Y.; Zhang, Y.; Xiao, W. The role of uPAR in epithelial-mesenchymal transition in small airway epi-thelium of patients with chronic obstructive pulmonary disease. Respir Res. 2013, 14, 67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Lester, R.D.; Jo, M.; Montel, V.; Takimoto, S.; Gonias, S.L. uPAR induces epithelial–mesenchymal transition in hypoxic breast cancer cells. J. Cell Biol. 2007, 178, 425–436. [Google Scholar] [CrossRef]
  107. Hannan, R.T.; Miller, A.E.; Hung, R.-C.; Sano, C.; Peirce, S.M.; Barker, T.H. Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition. Matrix Biol. Plus 2020, 10, 100056. [Google Scholar] [CrossRef]
  108. Katoh, D.; Kozuka, Y.; Noro, A.; Ogawa, T.; Imanaka-Yoshida, K.; Yoshida, T. Tenascin-C Induces Phenotypic Changes in Fibroblasts to Myofibroblasts with High Contractility through the Integrin αvβ1/Transforming Growth Factor β/SMAD Signaling Axis in Human Breast Cancer. Am. J. Pathol. 2020, 190, 2123–2135. [Google Scholar] [CrossRef]
  109. Bianchini, F.; Peppicelli, S.; Fabbrizzi, P.; Biagioni, A.; Mazzanti, B.; Menchi, G.; Calorini, L.; Pupi, A.; Trabocchi, A. Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells. Mol. Cell. Biochem. 2016, 424, 99–110. [Google Scholar] [CrossRef] [Green Version]
  110. Borok, Z. Role for α3 integrin in EMT and pulmonary fibrosis. J. Clin. Investig. 2008, 119, 7–10. [Google Scholar] [CrossRef]
  111. Shochet, G.E.; Brook, E.; Bardenstein-Wald, B.; Grobe, H.; Edelstein, E.; Israeli-Shani, L.; Shitrit, D. Integrin alpha-5 silencing leads to my-ofibroblastic differentiation in IPF-derived human lung fibroblasts. Ther. Adv. Chronic Dis. 2020, 24, 2040622320936023. [Google Scholar]
  112. Overstreet, J.M.; Wang, Y.; Wang, X.; Niu, A.; Gewin, L.S.; Yao, B.; Harris, R.C.; Zhang, M.Z. Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis. FASEB J. 2017, 31, 4407–4421. [Google Scholar] [CrossRef] [Green Version]
  113. Xu, H.; Liu, L.; Cong, M.; Liu, T.; Sun, S.; Ma, H.; You, H.; Jia, J.; Wang, P. EGF neutralization antibodies attenuate liver fibrosis by inhibiting myofi-broblast proliferation in bile duct ligation mice. Histochem. Cell Biol. 2020, 154, 107–116. [Google Scholar] [CrossRef]
  114. Shu, D.Y.; Lovicu, F.J. Enhanced EGF receptor-signaling potentiates TGFβ-induced lens epithelial-mesenchymal transition. Exp. Eye Res. 2019, 185, 107693. [Google Scholar] [CrossRef]
  115. Wu, S.; Yang, S.; Qu, H. circ_CHFR regulates ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by miR-15a-5p/EGFR axis in human brain microvessel endothelial cells. Open Life Sci. 2021, 16, 1053–1063. [Google Scholar] [CrossRef]
  116. Thooyamani, A.S.; Mukhopadhyay, A. PDGFRα mediated survival of myofibroblasts inhibit satellite cell proliferation during aberrant regeneration of lacerated skeletal muscle. Sci. Rep. 2021, 11, 1–15. [Google Scholar] [CrossRef]
  117. Jechlinger, M.; Sommer, A.; Moriggl, R.; Seither, P.; Kraut, N.; Capodiecci, P.; Donovan, M.; Cordon-Cardo, C.; Beug, H.; Grünert, S. Autocrine PDGFR signaling promotes mammary cancer metastasis. J. Clin. Investig. 2006, 116, 1561–1570. [Google Scholar] [CrossRef]
  118. Yan, D.; Liu, X.; Xu, H.; Guo, S.-W. Platelets induce endothelial–mesenchymal transition and subsequent fibrogenesis in endometriosis. Reprod. Biomed. Online 2020, 41, 500–517. [Google Scholar] [CrossRef]
  119. Chen, L.; Lin, G.; Chen, K.; Liang, R.; Wan, F.; Zhang, C.; Tian, G.; Zhu, X. VEGF promotes migration and invasion by regulating EMT and MMPs in nasopharyngeal carcinoma. J. Cancer 2020, 11, 7291–7301. [Google Scholar] [CrossRef]
  120. Modi, S.; Tiwari, A.; Kulkarni, V. Reversal of TGF-β-induced epithelial-mesenchymal transition in hepatocellular carcinoma by sorafenib, a VEGFR-2 and Raf kinase inhibitor. Curr. Res. Pharmacol. Drug. Discov. 2021, 2, 100014. [Google Scholar] [CrossRef]
  121. Rossato, F.A.; Su, Y.; Mackey, A.; Ng, Y.S.E. Fibrotic Changes and Endothelial-to-Mesenchymal Transition Promoted by VEGFR2 Antagonism Alter the Therapeutic Effects of VEGFA Pathway Blockage in a Mouse Model of Choroidal Neovascularization. Cells 2020, 9, 2057. [Google Scholar] [CrossRef] [PubMed]
  122. Sanders, Y.Y.; Cui, Z.; Le Saux, C.J.; Horowitz, J.C.; Rangarajan, S.; Kurundkar, A.; Antony, V.B.; Thannickal, V.J. SMAD-Independent Down-Regulation of Caveolin-1 by TGF-β: Effects on Proliferation and Survival of Myofibroblasts. PLoS ONE 2015, 10, e0116995. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Yang, S.; Zhao, J.; Huang, S.; Shu, B.; Yang, R.; Chen, L.; Xu, Y.; Xie, J.; Liu, X.; Jia, J. Reduced hydration-induced decreased caveolin-1 expression causes epithelial-to-mesenchymal transition. Am. J. Transl. Res. 2020, 12, 8067–8083. [Google Scholar] [PubMed]
  124. Jung, A.C.; Ray, A.M.; Ramolu, L.; Macabre, C.; Simon, F.; Noulet, F.; Blandin, A.F.; Renner, G.; Lehmann, M.; Choulier, L. Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties. Onco_target 2015, 6, 41884–41901. [Google Scholar] [CrossRef] [PubMed]
  125. Li, Z.; Wermuth, P.J.; Benn, B.S.; Lisanti, M.P.; Jimenez, S.A. Caveolin-1 Deficiency Induces Spontaneous Endothelial-to-Mesenchymal Transition in Murine Pulmonary Endothelial Cells in Vitro. Am. J. Pathol. 2012, 182, 325–331. [Google Scholar] [CrossRef]
  126. Schnieder, J.; Mamazhakypov, A.; Birnhuber, A.; Wilhelm, J.; Kwapiszewska, G.; Ruppert, C.; Markart, P.; Wujak, L.; Rubio, K.; Barreto, G. Loss of LRP1 promotes acquisition of contractile-myofibroblast phenotype and release of active TGF-β1 from ECM stores. Matrix Biol. 2019, 88, 69–88. [Google Scholar] [CrossRef]
  127. Hu, K.; Lin, L.; Tan, X.; Yang, J.; Bu, G.; Mars, W.M.; Liu, Y. tPA Protects Renal Interstitial Fibroblasts and Myofibroblasts from Apoptosis. J. Am. Soc. Nephrol. 2008, 19, 503–514. [Google Scholar] [CrossRef] [Green Version]
  128. Hu, K.; Wu, C.; Mars, W.M.; Liu, Y. Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor–related protein 1–mediated integrin signaling. J. Clin. Investig. 2007, 117, 3821–3832. [Google Scholar] [CrossRef] [Green Version]
  129. Omori, K.; Hattori, N.; Senoo, T.; Takayama, Y.; Masuda, T.; Nakashima, T.; Iwamoto, H.; Fujitaka, K.; Hamada, H.; Kohno, N. Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Transforming Growth Factor-β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts. PLoS ONE 2016, 11, e0148969. [Google Scholar] [CrossRef] [Green Version]
  130. Zhang, Y.P.; Wang, W.L.; Liu, J.; Li, W.B.; Bai, L.L.; Yuan, Y.D.; Song, S.X. Plasminogen activator inhibitor-1 promotes the proliferation and inhibits the apoptosis of pulmonary fibroblasts by Ca2+ signaling. Thromb. Res. 2012, 131, 64–71. [Google Scholar] [CrossRef]
  131. Masuda, T.; Nakashima, T.; Namba, M.; Yamaguchi, K.; Sakamoto, S.; Horimasu, Y.; Miyamoto, S.; Iwamoto, H.; Fujitaka, K.; Miyata, Y. Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts. J. Cell. Mol. Med. 2019, 23, 2984–2994. [Google Scholar] [CrossRef] [Green Version]
  132. Pedroja, B.; Kang, L.; Imas, A.; Carmeliet, P.; Bernstein, A. Plasminogen activator inhibitor-1 regulates integrin alphavbeta3 ex-pression and autocrine transforming growth factor beta signaling. J. Biol. Chem. 2009, 284, 20708–20717. [Google Scholar] [CrossRef] [Green Version]
  133. Ghosh, A.K.; Vaughan, D.E. PAI-1 in tissue fibrosis. J. Cell. Physiol. 2012, 227, 493–507. [Google Scholar] [CrossRef] [Green Version]
  134. Ghosh, A.K.; Bradham, W.S.; Gleaves, L.A.; De Taeye, B.; Murphy, S.B.; Covington, J.W.; Vaughan, D.E. Genetic deficiency of plasminogen activator inhibitor-1 promotes cardiac fibrosis in aged mice: Involvement of constitutive transforming growth factor-beta signaling and endothelial-to-mesenchymal transition. Circulation 2010, 122, 1200–1209. [Google Scholar] [CrossRef]
  135. Baumeier, C.; Escher, F.; Aleshcheva, G.; Pietsch, H.; Schultheiss, H.-P. Plasminogen activator inhibitor-1 reduces cardiac fibrosis and promotes M2 macrophage polarization in inflammatory cardiomyopathy. Basic Res. Cardiol. 2021, 116, 1–9. [Google Scholar] [CrossRef]
  136. Kanno, Y.; Kawashita, E.; Kokado, A.; Okada, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. Alpha2-antiplasmin regulates the development of dermal fibrosis in mice by prostaglandin F2α synthesis through adipose triglyceride lipase/calcium-independent phospho-lipase. Arthritis Rheum. 2013, 65, 492–502. [Google Scholar] [CrossRef]
  137. Kanno, Y.; Shu, E.; Niwa, H.; Seishima, M.; Ozaki, K.-I. MicroRNA-30c attenuates fibrosis progression and vascular dysfunction in systemic sclerosis model mice. Mol. Biol. Rep. 2021, 48, 3431–3437. [Google Scholar] [CrossRef]
  138. Kanno, Y.; Hirota, M.; Matsuo, O.; Ozaki, K.-I. α2-antiplasmin positively regulates endothelial-to-mesenchymal transition and fibrosis progression in diabetic nephropathy. Mol. Biol. Rep. 2021, 49, 205–215. [Google Scholar] [CrossRef]
  139. Michalczyk, K.; Cymbaluk-Płoska, A. Metalloproteinases in Endometrial Cancer-Are They Worth Measuring? Int. J. Mol. Sci. 2021, 22, 12472. [Google Scholar] [CrossRef]
  140. Lijnen, H.R. Matrix Metalloproteinases and Cellular Fibrinolytic Activity. Biochemistry 2002, 67, 92–98. [Google Scholar] [CrossRef]
  141. Newby, A.C. Metalloproteinase production from macrophages—A perfect storm leading to atherosclerotic plaque rupture and myocardial infarction. Exp. Physiol. 2016, 101, 1327–1337. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Okazaki, I.; Noro, T.; Tsutsui, N.; Yamanouchi, E.; Kuroda, H.; Nakano, M.; Yokomori, H.; Inagaki, Y. Fibrogenesis and Carcinogenesis in Nonalcoholic Steatohepatitis (NASH): Involvement of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinase (TIMPs). Cancers 2014, 6, 1220–1255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Young-Min, A.S.; Beeton, C.; Laughton, R.; Plumpton, T.; Bartram, S.; Murphy, G.; Black, C.; Cawston, E.T. Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud’s phenomenon, and in normal controls. Ann. Rheum. Dis. 2001, 60, 846–851. [Google Scholar] [PubMed]
  144. Yao, H.; Yang, X.; Yan, M.; Fang, X.; Wang, Y.; Qi, H.; Sun, L. Correlation of Serum M-CSF, CER, and TIMP-1 Levels with Liver Fibrosis in Viral Hepatitis. Comput. Math. Methods Med. 2022, 2022, 6736225. [Google Scholar] [CrossRef] [PubMed]
  145. Eguchi, A.; Iwasa, M.; Sugimoto, R.; Tempaku, M.; Yoshikawa, K.; Yoshizawa, N.; Povero, D.; Sugimoto, K.; Hasegawa, H.; Takei, Y. Complement complex 1 subunit q-mediated hepatic stellate cell activation with connective tissue growth factor elevation is a prognostic factor for survival in rat and human chronic liver diseases. Hepatol. Commun. 2022, 6, 3515–3527. [Google Scholar] [CrossRef]
  146. Lefeuvre, C.; Roux, M.; Blanchard, S.; Le Guillou-Guillemette, H.; Boursier, J.; Lunel-Fabiani, F.; Jeannin, P.; Pivert, A.; Ducancelle, A. Analysis of hepatic fibrosis markers in the serum of chronic hepatitis B patients according to basal core promoter/precore mutants. Sci. Rep. 2022, 12, 10261. [Google Scholar] [CrossRef]
  147. Yang, K.; Palm, J.; König, J.; Seeland, U.; Rosenkranz, S.; Feiden, W.; Rübe, C.; Rübe, C.E. Matrix-Metallo-Proteinases and their tissue inhibitors in radiation-induced lung injury. Int. J. Radiat. Biol. 2007, 83, 665–676. [Google Scholar] [CrossRef]
  148. Wang, Y.; Huang, G.; Mo, B.; Wang, C. Artesunate modulates expression of matrix metalloproteinases and their inhibitors as well as collagen-IV to attenuate pulmonary fibrosis in rats. Genet. Mol. Res. 2016, 15, 530. [Google Scholar] [CrossRef]
  149. Kökény, G.; Németh, Á.; Kopp, J.B.; Chen, W.; Oler, A.J.; Manzéger, A.; Rosivall, L.; Mózes, M.M. Susceptibility to kidney fibrosis in mice is associated with early growth response-2 protein and tissue inhibitor of metalloproteinase-1 expression. Kidney Int. 2022, 102, 337–354. [Google Scholar] [CrossRef]
  150. Takawale, A.; Zhang, P.; Patel, V.; Wang, X.; Oudit, G.; Kassiri, Z. Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myo-cardial Fibrosis by Mediating CD63-Integrin β1 Interaction. Hypertension 2017, 69, 1092–1103. [Google Scholar] [CrossRef]
  151. Kanno, Y.; Shu, E.; Niwa, H.; Kanoh, H.; Seishima, M. Alternatively activated macrophages are associated with the α2AP production that occurs with the development of dermal fibrosis: The role of alternatively activated macrophages on the development of fibrosis. Arthritis Res Ther. 2020, 22, 76. [Google Scholar] [CrossRef] [Green Version]
  152. Rabieian, R.; Boshtam, M.; Zareei, M.; Kouhpayeh, S.; Masoudifar, A.; Mirzaei, H. Plasminogen Activator Inhibitor Type-1 as a Regulator of Fibrosis. J. Cell Biochem. 2018, 119, 17–27. [Google Scholar] [CrossRef]
  153. Ueno, M.; Maeno, T.; Nomura, M.; Aoyagi-Ikeda, K.; Matsui, H.; Hara, K.; Tanaka, T.; Iso, T.; Suga, T.; Kurabayashi, M. Hypoxia-inducible factor-1α mediates TGF-β-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis. Am. J. Physiol. Cell. Mol. Physiol. 2011, 300, L740–L752. [Google Scholar] [CrossRef] [Green Version]
  154. Ma, L.; Fogo, A. PAI-1 and kidney fibrosis. Front. Biosci. 2009, 14, 2028–2041. [Google Scholar] [CrossRef]
  155. Liakouli, V.; Cipriani, P.; Marrelli, A.; Alvaro, S.; Ruscitti, P.; Giacomelli, R. Angiogenic cytokines and growth factors in systemic sclerosis. Autoimmun. Rev. 2011, 10, 590–594. [Google Scholar] [CrossRef]
  156. Mostmans, Y.; Cutolo, M.; Giddelo, C.; Decuman, S.; Melsens, K.; Declercq, H.; Vandecasteele, E.; De Keyser, F.; Distler, O.; Gutermuth, J. The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review. Autoimmun. Rev. 2017, 16, 774–786. [Google Scholar] [CrossRef]
  157. Zanin-Silva, D.C.; Santana-Gonçalves, M.; Kawashima-Vasconcelos, M.Y.; Oliveira, M.C. Management of Endothelial Dysfunction in Systemic Sclerosis: Current and Developing Strategies. Front. Med. 2021, 8, 250. [Google Scholar] [CrossRef]
  158. Plow, E.F.; Hoover-Plow, J. The Functions of Plasminogen in Cardiovascular Disease. Trends Cardiovasc. Med. 2004, 14, 180–186. [Google Scholar] [CrossRef]
  159. Mosesson, M.W. Fibrinogen and fibrin structure and functions. J. Thromb. Haemost. 2005, 3, 1894–1904. [Google Scholar] [CrossRef]
  160. Rundhaug, J.E. Matrix metalloproteinases and angiogenesis. J. Cell. Mol. Med. 2005, 9, 267–285. [Google Scholar] [CrossRef]
  161. Yan, Q.; Sage, E. Transforming growth factor-beta1 induces apoptotic cell death in cultured retinal endothelial cells but not pericytes: Association with decreased expression of p21waf1/cip. J. Cell Biochem. 1998, 70, 70–83. [Google Scholar] [CrossRef]
  162. Long, D.; Yang, J.; Wu, X.; Gui, Y.; Yu, L. Urokinase-type plasminogen activator protects human umbilical vein endothelial cells from apoptosis in sepsis. Int. J. Clin. Exp. Pathol. 2019, 12, 77–86. [Google Scholar] [PubMed]
  163. Prager, G.W.; Mihaly, J.; Brunner, P.M.; Koshelnick, Y.; Hoyer-Hansen, G.; Binder, B.R. Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis protein. Blood 2009, 113, 1383–1390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Song, T.; Meng, S.; Xu, S.-T.; Jin, S.-J.; Zeng, Q.-Z.; Gu, G.-J. The overexpression of uPA promotes the proliferation and fibrinolytic activity of human umbilical vein endothelial cells. Int. J. Clin. Exp. Pathol. 2019, 12, 2959–2966. [Google Scholar] [PubMed]
  165. Beloglazova, I.B.; Zubkova, E.S.; Stambol’skii, D.V.; Plekhanova, O.S.; Men’shikov, M.Y.; Akopyan, Z.A.; Bibilashvili, R.S.; Parfenova, E.V.; Tkachuk, V.A. Proteolytically inactive recom-binant forms of urokinase suppress migration of endothelial cells. Bull. Exp. Biol. Med. 2014, 156, 756–759. [Google Scholar] [CrossRef] [PubMed]
  166. Balsara, R.D.; Merryman, R.; Virjee, F.; Northway, C.; Castellino, F.J.; Ploplis, A.V. A deficiency of uPAR alters endothelial angiogenic function and cell morphology. Vasc. Cell 2011, 3, 10. [Google Scholar] [CrossRef] [Green Version]
  167. Lu, H.; Mabilat, C.; Yeh, P.; Guitton, J.D.; Li, H.; Pouchelet, M.; Shoevaert, D.; Legrand, Y.; Soria, J.; Soria, C. Blockage of urokinase receptor reduces in vitro the motility and the deformability of endothelial cells. FEBS Lett. 1996, 380, 21–24. [Google Scholar] [CrossRef] [Green Version]
  168. Beloglazova, I.; Stepanova, V.; Zubkova, E.; Dergilev, K.; Koptelova, N.; Tyurin-Kuzmin, P.A.; Dyikanov, D.; Plekhanova, O.; Cines, D.B.; Mazar, A.P. Mesenchymal stromal cells enhance self-assembly of a HUVEC tubular network through uPA-uPAR/VEGFR2/integrin/NOTCH crosstalk. Biochim. Biophys. Acta. Mol. Cell Res. 2022, 1869, 119157. [Google Scholar] [CrossRef]
  169. Alexander, R.A.; Prager, G.W.; Mihaly-Bison, J.; Uhrin, P.; Sunzenauer, S.; Binder, B.R.; Schütz, G.J.; Freissmuth, M.; Breuss, J.M. VEGF-induced endothelial cell migration requires urokinase receptor (uPAR)-dependent integrin redistribution. Cardiovasc. Res. 2012, 94, 125–135. [Google Scholar] [CrossRef] [Green Version]
  170. Reuning, U.; Sperl, S.; Kopitz, C.; Kessler, H.; Krüger, A.; Schmitt, M.; Magdolen, V. Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR): Development of Antagonists of uPA / uPAR Interaction and their Effects In Vitro and In Vivo. Curr. Pharm. Des. 2003, 9, 1529–1543. [Google Scholar] [CrossRef]
  171. Poettler, M.; Unseld, M.; Mihaly-Bison, J.; Uhrin, P.; Koban, F.; Binder, B.R.; Zielinski, C.C.; Prager, G.W. The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration. Thromb. Haemost. 2012, 108, 357–366. [Google Scholar] [CrossRef]
  172. Stepanova, V.; Jayaraman, P.S.; Zaitsev, S.V.; Lebedeva, T.; Bdeir, K.; Kershaw, R.; Holman, K.R.; Parfyonova, Y.V.; Semina, E.V.; Beloglazova, I.B. Urokinase-type Plasminogen Activator (uPA) Promotes Angiogenesis by Attenuating Proline-rich Homeodomain Protein (PRH) Transcription Factor Activity and De-repressing Vascular Endothelial Growth Factor (VEGF) Receptor Expression. J. Biol. Chem. 2016, 291, 15029–15045. [Google Scholar] [CrossRef] [Green Version]
  173. Raghu, H.; Nalla, A.K.; Gondi, C.S.; Gujrati, M.; Dinh, D.H.; Rao, J.S. uPA and uPAR shRNA inhibit angiogenesis via enhanced secretion of SVEGFR1 independent of GM-CSF but dependent on TIMP-1 in endothelial and glioblastoma cells. Mol. Oncol. 2011, 6, 33–47. [Google Scholar] [CrossRef] [Green Version]
  174. Park, J.; Keller, G.; Ferrara, N. The vascular endothelial growth factor (VEGF) isoforms: Differential deposition into the subep-ithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol. Biol. Cell. 1993, 4, 1317–1326. [Google Scholar] [CrossRef]
  175. Kanno, Y.; Shu, E.; Kanoh, H.; Matsuda, A.; Seishima, M. α2AP regulates vascular alteration by inhibiting VEGF signaling in systemic sclerosis: The roles of α2AP in vascular dysfunction in systemic sclerosis. Arthritis Res. Ther. 2017, 19, 1–8. [Google Scholar] [CrossRef] [Green Version]
  176. Herkenne, S.; Paques, C.; Nivelles, O.; Lion, M.; Bajou, K.; Pollenus, T.; Fontaine, M.; Carmeliet, P.; Martial, J.A.; Nguyen, N.Q. The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis. Sci. Signal. 2015, 8, ra117. [Google Scholar] [CrossRef]
  177. Larusch, G.A.; Merkulova, A.; Mahdi, F.; Shariat-Madar, Z.; Sitrin, R.G.; Cines, D.B.; Schmaier, A.H. Domain 2 of uPAR regulates single-chain uro-kinase-mediated angiogenesis through β1-integrin and VEGFR. Am. J. Physiol. Heart Circ. Physiol. 2013, 305, H305–H320. [Google Scholar] [CrossRef] [Green Version]
  178. LaRusch, G.A.; Mahdi, F.; Shariat-Madar, Z.; Adams, G.; Sitrin, R.G.; Zhang, W.M.; McCrae, K.R.; Schmaier, A.H. Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesis. Blood 2010, 115, 5111–5120. [Google Scholar] [CrossRef] [Green Version]
  179. D’Alessio, S.; Fibbi, G.; Cinelli, M.; Guiducci, S.; Del Rosso, A.; Margheri, F.; Serratì, S.; Pucci, M.; Kahaleh, B.; Fan, P. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum. 2004, 50, 3275–3285. [Google Scholar] [CrossRef]
  180. Bifulco, K.; Longanesi-Cattani, I.; Gala, M.; DICarluccio, G.; Masucci, M.T.; Pavone, V.; Lista, L.; Arra, C.; Stoppelli, M.P.; Carriero, M.V. The soluble form of urokinase receptor promotes angiogenesis through its Ser⁸⁸-Arg-Ser-Arg-Tyr⁹² chemotactic sequence. J. Thromb. Haemost. 2010, 8, 2789–2799. [Google Scholar] [CrossRef]
  181. Fuchs, P.Ö.; Calitz, C.; Pavlović, N.; Binet, F.; Solbak, S.M.Ø.; Danielson, U.H.; Kreuger, J.; Heindryckx, F.; Gerwins, P. Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment. Cell Signal. 2020, 72, 109661. [Google Scholar] [CrossRef] [PubMed]
  182. Schimmel, K.; Ichimura, K.; Reddy, S.; Haddad, F.; Spiekerkoetter, E. Cardiac Fibrosis in the Pressure Overloaded Left and Right Ventricle as a Therapeutic _target. Front. Cardiovasc. Med. 2022, 9, 6553. [Google Scholar] [CrossRef] [PubMed]
  183. Liu, S.-F.; Veetil, N.N.; Li, Q.; Kucherenko, M.M.; Knosalla, C.; Kuebler, W.M. Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening. Front. Immunol. 2022, 13, 209. [Google Scholar] [CrossRef] [PubMed]
  184. Christou, H.; Khalil, R.A. Mechanisms of pulmonary vascular dysfunction in pulmonary hypertension and implications for novel therapies. Am. J. Physiol. Circ. Physiol. 2022, 322, H702–H724. [Google Scholar] [CrossRef] [PubMed]
  185. Ban, C.; Wang, T.; Zhang, S.; Xin, P.; Liang, L.; Wang, C.; Dai, H. Fibrinolytic system related to pulmonary arterial pressure and lung function of patients with idiopathic pulmonary fibrosis. Clin. Respir. J. 2015, 11, 640–647. [Google Scholar] [CrossRef]
  186. Levi, M.; Moons, L.; Bouché, A.; Shapiro, S.D.; Collen, D.; Carmeliet, P. Deficiency of Urokinase-Type Plasminogen Activator–Mediated Plasmin Generation Impairs Vascular Remodeling During Hypoxia-Induced Pulmonary Hypertension in Mice. Circulation 2001, 103, 2014–2020. [Google Scholar] [CrossRef]
  187. Manetti, M.; Allanore, Y.; Revillod, L.; Fatini, C.; Guiducci, S.; Cuomo, G.; Bonino, C.; Riccieri, V.; Bazzichi, L.; Liakouli, V. A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis. Arthritis Rheum. 2010, 63, 247–256. [Google Scholar] [CrossRef]
  188. Makarova, A.M.; Lebedeva, T.V.; Nassar, T.; Higazi, A.A.; Xue, J.; Carinato, M.E.; Bdeir, K.; Cines, D.B.; Stepanova, V. Urokinase-type Plasminogen Activator (uPA) Induces Pulmonary Microvascular Endothelial Permeability through Low Density Lipoprotein Receptor-related Protein (LRP)-dependent Activation of Endothelial Nitric-oxide Synthase. J. Biol. Chem. 2011, 286, 23044–23053. [Google Scholar] [CrossRef] [Green Version]
  189. Boccella, S.; Panza, E.; Lista, L.; Belardo, C.; Ianaro, A.; De Rosa, M.; de Novellis, V.; Pavone, V. Preclinical evaluation of the urokinase receptor-derived peptide UPARANT as an anti-inflammatory drug. Inflamm. Res. 2017, 66, 701–709. [Google Scholar] [CrossRef]
  190. Yoon, S.Y.; Lee, Y.J.; Seo, J.H.; Sung, H.J.; Park, K.H.; Choi, I.K.; Kim, S.J.; Oh, S.C.; Choi, C.W.; Kim, B.S. uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line. Cell Res. 2006, 16, 75–81. [Google Scholar] [CrossRef] [Green Version]
  191. Huang, E.; Peng, N.; Xiao, F.; Hu, D.; Wang, X.; Lu, L. The Roles of Immune Cells in the Pathogenesis of Fibrosis. Int. J. Mol. Sci. 2020, 21, 5203. [Google Scholar] [CrossRef]
  192. Abdul, S.; Leebeek, F.; Rijken, D.; Uitte de Willige, S. Natural heterogeneity of α2-antiplasmin: Functional and clinical conse-quences. Blood 2016, 127, 538–545. [Google Scholar] [CrossRef] [Green Version]
  193. Van Geffen, C.; Deißler, A.; Quante, M.; Renz, H.; Hartl, D.; Kolahian, S. Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes? Front. Immunol. 2021, 22, 663203. [Google Scholar] [CrossRef]
  194. Brown, M.; O’Reilly, S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin. Exp. Immunol. 2018, 195, 310–321. [Google Scholar] [CrossRef]
  195. Pattanaik, D.; Brown, M.; Postlethwaite, B.; Postlethwaite, A. Pathogenesis of Systemic Sclerosis. Front Immunol. 2015, 6, 272. [Google Scholar] [CrossRef] [Green Version]
  196. Numajiri, H.; Kuzumi, A.; Fukasawa, T.; Ebata, S.; Yoshizaki-Ogawa, A.; Asano, Y.; Kazoe, Y.; Mawatari, K.; Kitamori, T.; Yoshizaki, A. B Cell Depletion Inhibits Fibrosis via Suppression of Profibrotic Macrophage Differentiation in a Mouse Model of Systemic Sclerosis. Arthritis Rheumatol. 2021, 73, 2086–2095. [Google Scholar] [CrossRef]
  197. Nakayama, W.; Jinnin, M.; Makino, K.; Kajihara, I.; Makino, T.; Fukushima, S.; Inoue, Y.; Ihn, H. Serum levels of soluble CD163 in patients with systemic sclerosis. Rheumatol. Int. 2010, 32, 403–407. [Google Scholar] [CrossRef]
  198. Wang, X.; Chen, J.; Xu, J.; Xie, J.; Harris, D.C.H.; Zheng, G. The Role of Macrophages in Kidney Fibrosis. Front. Physiol. 2021, 12, 5838. [Google Scholar] [CrossRef]
  199. Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958–969. [Google Scholar] [CrossRef]
  200. Mondino, A.; Blasi, F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol. 2004, 25, 450–455. [Google Scholar] [CrossRef]
  201. Syrovets, T.; Lunov, O.; Simmet, T. Plasmin as a proinflammatory cell activator. J. Leukoc. Biol. 2012, 92, 509–519. [Google Scholar] [CrossRef] [PubMed]
  202. Medcalf, R.; Keragala, C. Fibrinolysis: A Primordial System Linked to the Immune Response. Int. J. Mol. Sci. 2021, 22, 3406. [Google Scholar] [CrossRef] [PubMed]
  203. Hastings, S.; Myles, P.; Medcalf, R. Plasmin, Immunity, and Surgical Site Infection. J. Clin. Med. 2021, 10, 2070. [Google Scholar] [CrossRef] [PubMed]
  204. Vago, J.P.; Sugimoto, M.A.; Lima, K.M.; Negreiros-Lima, G.L.; Baik, N.; Teixeira, M.M.; Perretti, M.; Parmer, R.J.; Miles, L.A.; Sousa, L.P. Plasminogen and the Plasminogen Receptor, Plg-RKT, Regulate Macrophage Phenotypic, and Functional Changes. Front. Immunol. 2019, 10, 1458. [Google Scholar] [CrossRef] [PubMed]
  205. Shimazu, H.; Munakata, S.; Tashiro, Y.; Salama, Y.; Dhahri, D.; Eiamboonsert, S.; Ota, Y.; Onoda, H.; Tsuda, Y.; Okada, Y. Pharmacological _targeting of plasmin prevents lethality in a murine model of macrophage activation syndrome. Blood 2017, 130, 59–72. [Google Scholar] [CrossRef] [Green Version]
  206. Li, X.; Syrovets, T.; Genze, F.; Pitterle, K.; Oberhuber, A.; Orend, K.H.; Simmet, T. Plasmin Triggers Chemotaxis of Monocyte-Derived Dendritic Cells Through an Akt2-Dependent Pathway and Promotes a T-Helper Type-1 Response. Arter. Thromb. Vasc. Biol. 2010, 30, 582–590. [Google Scholar] [CrossRef] [Green Version]
  207. Bryer, S.C.; Fantuzzi, G.; Van Rooijen, N.; Koh, T.J. Urokinase-Type Plasminogen Activator Plays Essential Roles in Macrophage Chemotaxis and Skeletal Muscle Regeneration. J. Immunol. 2008, 180, 1179–1188. [Google Scholar] [CrossRef] [Green Version]
  208. Meznarich, J.; Malchodi, L.; Helterline, D.; Ramsey, S.A.; Bertko, K.; Plummer, T.; Plawman, A.; Gold, E.; Stempien-Otero, A. Urokinase Plasminogen Activator Induces Pro-Fibrotic/M2 Phenotype in Murine Cardiac Macrophages. PLoS ONE 2013, 8, e57837. [Google Scholar] [CrossRef]
  209. Liu, G.; Yang, Y.; Yang, S.; Banerjee, S.; De Freitas, A.; Friggeri, A.; Davis, K.I.; Abraham, E. The receptor for urokinase regulates TLR2 mediated in-flammatory responses in neutrophils. PLoS ONE 2011, 6, e25843. [Google Scholar]
  210. Li, J.; Pan, Y.; Li, D.; Xia, X.; Jiang, Q.; Dou, H.; Hou, Y. Urokinase-type plasminogen activator receptor is required for impairing toll-like receptor 7 signaling on macrophage efferocytosis in lupus. Mol. Immunol. 2020, 127, 38–45. [Google Scholar] [CrossRef]
  211. Kiyan, Y.; Tkachuk, S.; Rong, S.; Gorrasi, A.; Ragno, P.; Dumler, I.; Haller, H.; Shushakova, N. TLR4 Response to LPS Is Reinforced by Urokinase Receptor. Front. Immunol. 2020, 11, 3550. [Google Scholar] [CrossRef]
  212. Rasmussen, L.J.H.; Petersen, J.E.V.; Eugen-Olsen, J. Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Biomarker of Systemic Chronic Inflammation. Front. Immunol. 2021, 12, 641. [Google Scholar] [CrossRef]
  213. Yousif, A.M.; Minopoli, M.; Bifulco, K.; Ingangi, V.; Di Carluccio, G.; Merlino, F.; Motti, M.L.; Grieco, P.; Carriero, M.V. Cyclization of the Urokinase Receptor-Derived Ser-Arg-Ser-Arg-Tyr Peptide Generates a Potent Inhibitor of Trans-Endothelial Migration of Monocytes. PLoS ONE 2015, 10, e0126172. [Google Scholar] [CrossRef]
Ijms 24 01796 g001 550
Figure 1. The mechanism of fibrosis progression.
Figure 1. The mechanism of fibrosis progression.
Ijms 24 01796 g001
Ijms 24 01796 g002 550
Figure 2. The functions of plasmin.
Figure 2. The functions of plasmin.
Ijms 24 01796 g002
Ijms 24 01796 g003 550
Figure 3. The structure of uPAR.
Figure 3. The structure of uPAR.
Ijms 24 01796 g003
Ijms 24 01796 g004 550
Figure 4. The multiple functions of uPAR.
Figure 4. The multiple functions of uPAR.
Ijms 24 01796 g004
Ijms 24 01796 g005 550
Figure 5. uPAR expression in fibrosis-related diseases [56,57,58,59,60,61,62,63].
Figure 5. uPAR expression in fibrosis-related diseases [56,57,58,59,60,61,62,63].
Ijms 24 01796 g005
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kanno, Y. The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression. Int. J. Mol. Sci. 2023, 24, 1796. https://doi.org/10.3390/ijms24021796

AMA Style

Kanno Y. The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression. International Journal of Molecular Sciences. 2023; 24(2):1796. https://doi.org/10.3390/ijms24021796

Chicago/Turabian Style

Kanno, Yosuke. 2023. "The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression" International Journal of Molecular Sciences 24, no. 2: 1796. https://doi.org/10.3390/ijms24021796

APA Style

Kanno, Y. (2023). The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression. International Journal of Molecular Sciences, 24(2), 1796. https://doi.org/10.3390/ijms24021796

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop
  NODES
admin 2
Association 4
Idea 2
idea 2
innovation 2
INTERN 36
Note 9
Project 1
twitter 1