Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Biomarker of Systemic Chronic Inflammation

Line Jee Hartmann Rasmussen, Jens Emil Vang Petersen, Jesper Eugen-Olsen, Line Jee Hartmann Rasmussen, Jens Emil Vang Petersen, Jesper Eugen-Olsen

Abstract

Systemic chronic inflammation (SCI) is persistent, health-damaging, low-grade inflammation that plays a major role in immunosenescence and in development and progression of many diseases. But currently, there are no recognized standard biomarkers to assess SCI levels alone, and SCI is typically measured by combining biomarkers of acute inflammation and infection, e.g., CRP, IL-6, and TNFα. In this review, we highlight 10 properties and characteristics that are shared by the blood protein soluble urokinase plasminogen activator receptor (suPAR) and SCI, supporting the argument that suPAR is a biomarker of SCI: (1) Expression and release of suPAR is upregulated by immune activation; (2) uPAR and suPAR exert pro-inflammatory functions; (3) suPAR is associated with the amount of circulating immune cells; (4) Blood suPAR levels correlate with the levels of established inflammatory biomarkers; (5) suPAR is minimally affected by acute changes and short-term influences, in contrast to many currently used markers of systemic inflammation; (6) Like SCI, suPAR is non-specifically associated with multiple diseases; (7) suPAR and SCI both predict morbidity and mortality; (8) suPAR and SCI share the same risk factors; (9) suPAR is associated with risk factors and outcomes of inflammation above and beyond other inflammatory biomarkers; (10) The suPAR level can be reduced by anti-inflammatory interventions and treatment of disease. Assessing SCI has the potential to inform risk for morbidity and mortality. Blood suPAR is a newer biomarker which may, in fact, be a biomarker of SCI since it is stably associated with inflammation and immune activation; shares the same risk factors as many age-related diseases; is both elevated by and predicts age-related diseases. There is strong evidence that suPAR is a prognostic marker of adverse events, morbidity, and mortality. It is associated with immune activity and prognosis across diverse conditions, including kidney disease, cardiovascular disease, cancer, diabetes, and inflammatory disorders. Thus, we think it likely represents a common underlying disease-process shared by many diseases; that is, SCI. We review the supporting literature and propose a research agenda that can help test the hypothesis that suPAR indexes SCI, with the potential of becoming the new gold standard for measuring SCI.

Keywords: C-reactive protein; biomarkers; immunosenescence; inflammaging; inflammation; inflammation mediators - blood; interleukin-6.

Conflict of interest statement

JE-O is a named inventor on patents on suPAR as a prognostic biomarker. The patents are owned by Copenhagen University Hospital Amager and Hvidovre, Denmark, and is licensed to ViroGates A/S. JE-O is a co-founder, shareholder, and CSO of ViroGates A/S. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Rasmussen, Petersen and Eugen-Olsen.

Figures

Figure 1
Figure 1
Inflammatory functions of uPAR and suPAR. Upon an inflammatory stimulus, e.g., stimulation of toll-like receptors (TLRs) or cytokine receptors, the expression of urokinase plasminogen activator receptor (uPAR) in immunologically active cells is increased via activation of transcription factors, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP1), which bind to the promoter region of the PLAUR gene. The uPAR mRNA is either degraded (by p53) or stabilized for translation (by HuR or hnRNPC), after which uPAR is expressed at the cell surface, bound to the membrane via a glycosyl phosphatidylinositol (GPI) anchor. At the cell surface, uPAR can become cleaved by various proteases or its own ligand urokinase plasminogen activator (uPA), thus generating suPAR, which plays a role in inflammation by impairing neutrophil efferocytosis and stimulating angiogenesis and chemotaxis. Active uPA cleaves plasminogen to plasmin, which in turn cleaves and activates uPA. Plasmin activates matrix metalloproteases (MMPs), cleaves extracellular matrix (ECM) components, degrades fibrin, and activates the classical complement pathway, thereby promoting migration and invasion of cells, fibrinolysis, vasodilation, opsonization, and phagocytosis of foreign pathogens. Co-localization of uPAR with the proteins cytokeratin-1 (CK1) and globular C1q receptor (gC1qR) on the surface of endothelial cells also promotes vasodilation through release of bradykinin via activation of kallikrein. In a complex with β2 integrin and gC1qR, uPAR also induces release of cytokines (IL-1β, IL-6, TNFα) and chemokines (IL-8, MCP-1), upon stimulation by cleaved high molecular weight kininogen (HKa). Cytokines stimulate the production of C-reactive protein (CRP) from the liver, and CRP itself functions as an opsonin and also activates the classical complement pathway. Furthermore, uPAR interacts with vitronectin, fibrinogen, and integrins, mainly αMβ2 integrin (Mac-1) but also β1 and β3 integrin complexes, activating intracellular signaling pathways that facilitate cell adhesion, migration, invasion, proliferation, and survival by affecting F-actin assembly and gene transcription. The activity of uPA and plasmin is inhibited by plasminogen activator inhibitor (PAI)-1, PAI-2, and α2-antiplasmin. Binding of PAI-1 and low-density lipoprotein receptor-related protein 1 (LRP1) mediates endocytosis of uPAR-uPA-PAI-1 complexes, followed by lysosomal degradation of uPA and PAI-1 and recycling of uPAR back to the membrane. In endothelial cells, co-localization of uPAR with CK1 and gC1qR activates kallikrein and promotes the release of the vasodilator bradykinin. hnRNPC, heterogeneous nuclear ribonucleoprotein C; HuR, Hu antigen R; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; TNFα, tumor necrosis factor α. Adapted from Rasmussen, LJH (2018) (19) with permission.
Figure 2
Figure 2
Structure of uPAR and suPAR isoforms. Soluble urokinase plasminogen activator receptor (suPAR) is the soluble form of the membrane-bound receptor uPAR, which is tethered to the membrane by a glycosyl phosphatidylinositol (GPI) anchor. The protein consists of three domains, D1-D3, that are connected with a linker region between D1 and D2D3. Several cleavage sites exist, both in the linker region and the GPI anchor, and proteolytic cleavage generates three suPAR isoforms: full-length suPARI-III, suPARI, and suPARII-III. Cleavage of uPAR/suPAR in the linker region exposes an SRSRY sequence, which is involved in chemotaxis. Reprinted from Rasmussen, LJH (2018) (19) with permission.
Figure 3
Figure 3
Functions of suPAR. The urokinase plasminogen activator receptor (uPAR) is expressed on the surface of immune cells, endothelial cells, and vascular smooth muscle cells, and proteolytic cleavage in the linker region or glycosyl phosphatidylinositol (GPI) anchor of uPAR generates soluble uPAR (suPAR). Various functions of suPAR have been proposed, including inhibition of neutrophil efferocytosis; binding of urokinase plasminogen activator (uPA) and vitronectin; stimulation of angiogenesis via endothelial sprouting and tube formation; promoting chemotaxis; and interactions with β3 integrin, which is suggested to cause podocyte injury in the glomeruli. Adapted from Rasmussen, LJH (2018) (19) with permission.
Figure 4
Figure 4
Overview of diseases with elevated suPAR levels. Clinical studies have shown that suPAR levels are elevated and associated with disease severity and prognosis in many diseases, including diseases of the brain, liver, kidneys, and respiratory system, cardiovascular disease, diabetes (type 1 and type 2), cancer as well as infectious, rheumatic, and psychiatric disorders. COVID-19, coronavirus disease 2019; FSGS, focal segmental glomerulosclerosis; HIV, human immunodeficiency virus; suPAR, soluble urokinase plasminogen activator receptor. Created with BioRender.com.
Figure 5
Figure 5
Levels of CRP, IL-6, and suPAR in the three inflammation groups identified by latent class analysis in the E-Risk study (n=1,390). Panels on the left show boxplots (box indicates median and interquartile range, and whiskers indicate 95% confidence interval) of untransformed C-reactive protein (CRP), interleukin-6 (IL-6), and soluble urokinase plasminogen activator receptor (suPAR) levels in the three groups, while the panel on the right shows mean Z-scores with standard deviations (M=0, SD=1). Group 1 (n=1,057) consisted of individuals with low CRP, IL-6, and suPAR. Group 2 (n=249) consisted of individuals with high CRP and IL-6 and moderately elevated suPAR. Group 3 (n=84) consisted of individuals with elevated CRP and IL-6 and high suPAR. Data from Rasmussen LJH, et al. (2020) (163).

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