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The urokinase-type plasminogen activator receptor (uPAR) modifies intracellular and extracellular pathways. uPAR is a GPI-linked membrane protein that modifies intracellular downstream pathway responses via protein-to-protein interactions in a large lipid raft of associated membrane proteins. uPAR modifies intracellular activation through interactions with integrins and GPCRs, as illustrated here. Mammalian serpin PAI-1 binding to the uPA/uPAR complex inhibits uPA/uPAR activity and can also be internalized, further modifying and altering intracellular activity pathways. uPA/uPAR also modifies extracellular activity via activation of plasminogen to form plasmin, with subsequent activation of MMPs and growth factors that alter cellular invasion into the extracellular matrix surrounding adjacent cells. The virus-derived serpin Serp-1 also binds and inhibits uPA and the uPAR as well as plasmin. MMP—matrix metalloproteinases; GPCR—G protein-coupled receptor; PAI—plasminogen activator inhibitor; C—complement; Vn—vitronectin; GPI—glycophosphatidyl inostitol; ECM—extracellular matrix; Serp-1—virus-derived serpin.
Source publication
The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex ha...
Citations
... The biomarker sCD14ST was suggested as a useful prognostic tool with which to predict SARS-CoV-2 outcomes in association with new-generation makers, such as SuPAR (soluble urokinase plasminogen activator receptor) [2,3]. SuPAR is a soluble molecule that can easily be measured in plasma and serum, reflecting the level of immune system activation [7,8], and recent evidence has suggested its potential role as a predictor of COVID-19 outcomes [9][10][11]. One of the challenging aspects of COVID-19 is its complex disease mechanism; COVID-19 can affect different organs, making it hard to identify biomarkers that capture the full effect of the disease [12,13]. ...
Background/Objectives: The COVID-19 pandemic has increased interest in osteoimmunology because of the impact of SARS-CoV-2 on both the immune system and the bone microenvironment. Soluble CD14ST could influence the production of the osteoimmunological regulators of osteoclast differentiation. The aim of this study is to evaluate the role of sCD14ST in COVID-19’s effects on bone remodeling—evaluating, in particular, the correlation with new-generation osteoimmunological biomarkers—and to acquire comprehensive knowledge of the effects of the disease on the immune and skeletal system. Methods: The serum level of sCD14ST was measured in COVID-19-positive and COVID-19-negative patients undergoing orthopedic surgery and correlated with the inflammatory and osteoimmunological biomarkers RANKL/OPG, FGF23, IL-6, C-reactive protein (CRP), procalcitonin (PCT), sRAGE, and SuPAR. Results: In our patients, sCD14ST showed a strong increase in COVID-19-positive patients, and a significant decrease in tandem with the infection resolution, confirming its diagnostic and prognostic value. sCD14ST was more clinically relevant than the two canonically inflammatory makers used in the clinical protocols, CRP and PCT, and displayed a good positive correlation with FGF23, RANKL/OPG, IL-6, and SuPAR and a negative correlation with sRAGE. Conclusions: Monitoring sCD14ST along with SuPAR may offer valuable insights into immune system dysregulation and bone-related complications in conditions characterized by inflammation. These soluble receptors represent important links between immune activation and bone metabolism, especially in the context of diseases like COVID-19, where the inflammatory response may impact bone fragility.
... For instance, the binding of the inactive proenzyme form (pro-uPA) to uPAR can also initiate plasmin activation [51]. Additionally, intracellular signaling can be mediated through other receptors such as vitronectin and integrins [52]. This indicates that uPAR's role extends beyond uPA binding, emphasizing its continuous availability during the wound-healing process. ...
Background/Objectives: There is a growing interest in the research of wound healing mechanisms worldwide. Particular attention has been paid to the expression of tissue remodeling- and inflammation-related factors. Herein, we investigate the expression patterns of TGF-β1, IL-6, TNF-a, uPA, uPA receptors, MMP-2, and MMP-9 through the four phases of the normal wound-healing process in humans. Methods: Twenty-two individuals presenting with a first episode of pilonidal sinus underwent surgical excision and the wound was left to heal by secondary intention. Sequential biopsies were collected on day 0 (operation), day 2 (inflammatory phase), day 9 (proliferative phase), and day 14 (tissue remodeling phase). The expression levels of the proteins were evaluated using reverse transcription–quantitative PCR. Statistical analyses were performed using GraphPad Prism software. One-way analysis of variance (ANOVA) with Dunn’s Multiple Comparison post hoc test was used. Results: The results showed statistically significant differences in the expressions of the factors during wound healing (p < 0.05). TGF-b1 increased on days 2 and 9. TNF-a increased on day 2 and then decreased on day 9. Il-6 was increased on day 2 and decreased on days 9 and 14. uPa mRNA increased up to day 9 but its receptor exhibited high expression throughout the observation time. Finally, MMP-2 mRNA expression increased on day 2 and declined on days 9 and 14, while MMP-9 was highly expressed until the 14th postoperative day. Conclusions: Each factor investigated in this study has an important and distinct role in the normal wound repair procedure. Further investigation is required to evaluate the tissue-specific regulation of these factors and their potential use as therapeutic targets or prognostic biomarkers in wound healing.
... Previous studies have also demonstrated the coordinated upregulation of uPAR and its ligand uPA in CD during intestinal epithelial barrier breakdown, where disrupted tight junctions and increased cell death suggest that the uPA-uPAR complex may affect the mucosal barrier by mediating PCD in target cells, identifying it as a potential CD target. Moreover, the high expression of uPA-uPAR in anti-TNF-resistant patients implies that the uPA-uPAR pathway may play an important role in these patients (Hamada et al., 2024;Cheng et al., 2022). Therefore, small molecule inhibitors or antibodies targeting uPA binding sites on uPAR may be beneficial to the development of CD therapy. ...
Background
Crohn’s disease (CD) is an immune-mediated disorder characterized by immune cell infiltration that induces persistent chronic inflammation of the gastrointestinal tract. Programmed cell death (PCD) plays a critical role in the pathogenesis of CD. This study identified vital PCD-related genes in CD based on immune infiltration using bioinformatic analysis.
Methods
We obtained two CD datasets from the Gene Expression Omnibus (GEO) database and examined immune cell infiltration to investigate immune cell dysregulation in CD. PCD-related genes were retrieved from the GeneCards database. Based on the differentially expressed genes (DEGs) and PCD gene sets, PCD-related DEGs were identified. Candidate hub genes were identified using a protein-protein interaction (PPI) network, and their diagnostic effectiveness was predicted using receiver operating characteristic (ROC) curve analysis. Functional enrichment and immune infiltration analyses were used to assess the distinct roles of the hub genes. Finally, the miRWalk and ENCORI databases were used to predict which microRNAs (miRNAs) regulated the hub genes and to verify gene expression in CD colonic tissues via transcriptome sequencing.
Results
A total of 335 PCD-related DEGs and 3 hub genes (MMP1, SAA1, and PLAU) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses indicated the enrichment of these genes in the immune response. Infiltration analysis of immune cells showed abundant endothelial cells, plasma cells, dendritic cells, and monocytes in the CD samples. Based on the correlation analysis, the three hub genes were positively correlated with monocytes and negatively correlated with CD8 naïve T-cells. MMP1, SAA1, and PLAU correlated with the pathogenicity of CD and had good diagnostic value for CD. The three hub genes were highly expressed in the CD tissues, as confirmed using transcriptome sequencing.
Conclusion
This study identified MMP1, SAA1, and PLAU as hub genes involved in PCD in patients with CD. These genes regulate immune cell function and their expression levels are closely related to immune cell infiltration. These findings provide novel insights into the mechanisms underlying CD pathogenesis. The identified PCD genes and regulatory miRNAs are potential biomarkers and therapeutic targets for CD.
... While our studies were largely focused on MSC, we show that at least monocytes/macrophages 14,15 , endothelial cells, major producers of tPA, for instance in vascular niches of the BMM or hepatic sinusoids, and fibroblasts participate in plasminogen activation, but contributions of other cell types cannot be excluded. Furthermore, consistent with the increase of plasminogen in B-ALL, uPAR, an important component of the plasminogen activation system and contributor to ECM lysis 49 , was also increased. Future studies are needed to address the role of this and the PAR pathways to B-ALL. ...
Fibrinolysis influences the mobilization of hematopoietic stem cells from their bone marrow microenvironment (BMM). Here we show that activation of plasmin, a key fibrinolytic agent, by annexin A2 (ANXA2) distinctly impacts progression of BCR-ABL1⁺ B-cell acute lymphoblastic leukemia (B-ALL) via modulation of the extracellular matrix (ECM) in the BMM. The dense ECM in a BMM with decreased plasmin activity entraps insulin-like growth factor (IGF) 1 and reduces mTORC2-dependent signaling and proliferation of B-ALL cells. Conversely, B-ALL conditions the BMM to induce hepatic generation of plasminogen, the plasmin precursor. Treatment with ε-aminocaproic acid (EACA), which inhibits plasmin activation, reduces tumor burden and prolongs survival, including in xenogeneic models via increased fibronectin in the BMM. Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated. Our studies suggest that fibrinolysis-mediated ECM remodeling and subsequent growth factor release influence B-ALL progression and inhibition of this process by EACA may be beneficial as adjunct therapy.
Chronic kidney disease–mineral and bone disorder (CKD-MBD) is a systemic complication of chronic kidney disease (CKD), resulting in high morbidity and mortality. However, effective treatment strategies are lacking. The pathogenesis of CKD-MBD is unclear but involves feedback mechanisms between calcium, phosphorus, parathyroid hormone, vitamin D and other factors, in addition to FGF23, Klotho, Wnt inhibitors, and activin A. Construction of a perfect animal model of CKD-MBD with clinical characteristics is important for in-depth study of disease development, pathological changes, targeted drug screening, and management of patients. Currently, the modeling methods of CKD-MBD include surgery, feeding and radiation. Additionally, the method of CKD-MBD modeling by surgical combined feeding is worth promoting because of short time, simplicity, and low mortality. Therefore, this review based on the pathogenesis and clinical features of CKD-MBD, combined with the current status of animal models, outlines the advantages and disadvantages of modeling methods, and provides a reference for further CKD-MBD research.
Hemostasis is a mechanism that stops bleeding from an injured vessel, involves multiple interlinked steps, culminating in the formation of a “clot” sealing the damaged area. Moreover, it has long been recognized that inflammation also provokes the activation of the coagulation system. However, there has been an increasing amount of evidence revealing the immune function of the hemostasis system. This review collects and analyzes the results of the experimental studies and data from clinical observations confirming the inflammatory function of hemostasis. Here, we summarize the latest knowledge of the pathways in immune system activation under the influence of coagulation factors. The data analyzed allow us to consider the components of hemostasis as receptors recognizing «foreign» or damaged «self» or/and as «self» damage signals that initiate and reinforce inflammation and affect the direction of the adaptive immune response. To sum up, the findings collected in the review allow us to classify the coagulation factors, such as Damage-Associated Molecular Patterns that break down the conventional concepts of the coagulation system.
Senescent cells accumulate throughout the body with advanced age, diseases and chronic conditions. They negatively impact health and function of multiple systems, including the central nervous system (CNS). Therapies that target senescent cells, broadly referred to as senotherapeutics, recently emerged as potentially important treatment strategies for the CNS. Promising therapeutic approaches involve clearing senescent cells by disarming their pro-survival pathways with 'senolytics'; or dampening their toxic senescence-associated secretory phenotype (SASP) using 'senomorphics'. Following the pioneering discovery of first-generation senolytics dasatinib and quercetin, dozens of additional therapies have been identified, and several promising targets are under investigation. Although potentially transformative, senotherapies are still in early stages and require thorough testing to ensure reliable target engagement, specificity, safety and efficacy. The limited brain penetrance and potential toxic side effects of CNS-acting senotherapeutics pose challenges for drug development and translation to the clinic. This Review assesses the potential impact of senotherapeutics for neurological conditions by summarizing preclinical evidence, innovative methods for target and biomarker identification, academic and industry drug development pipelines and progress in clinical trials.
