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.
Highlights
Systemic chronic inflammation (SCI) refers to persistent, lowgrade inflammation, and it is involved in the pathogenesis of a wide variety of chronic non-communicable diseases that collectively constitute the leading cause of death globally [1]
We propose that the blood levels of the protein soluble urokinase plasminogen activator receptor is a robust biomarker of SCI, with potential to be the new gold standard for measuring SCI. suPAR has been found to be a broad prognostic biomarker associated with incident disease and adverse clinical outcomes across both general and patient populations. suPAR has been reviewed as a marker of kidney disease, sepsis, cardiovascular disease, and inflammatory disorders [10,11,12,13]—but given its nonspecific associations with immune activity and prognosis in very diverse diseases and conditions, it is not a diseasespecific diagnostic marker
In a recent genome-wide association study, we found that blood suPAR levels were under substantial genetic influence [30], with a heritability estimate of 60% and 13 independently genomewide significant sequence variants associated with suPAR across 11 distinct loci
Summary
Systemic chronic inflammation (SCI) refers to persistent, lowgrade inflammation, and it is involved in the pathogenesis of a wide variety of chronic non-communicable diseases that collectively constitute the leading cause of death globally [1]. A biomarker of SCI needs to accurately and reliably capture the level of SCI; it should be correlated with other measures of inflammation, without being overshadowed by any acute inflammation or other short-term influences It should be measured; stable over long time periods in vitro and in vivo (i.e., high test-retest reliability and temporal stability); and independent of smaller day-to-day variations, such as circadian/ diurnal rhythm and fasting, while still being sensitive to significant contributions of psychosocial, environmental, and lifestyle factors as well as onset—or resolution—of chronic pathological processes. Associated variants were found in and around PLAUR as well as the gene encoding the uPAR ligand urokinase plasminogen activator (uPA, or urokinase) PLAU, the kidneydisease-associated gene PLA2R1, and genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response [30] This indicates that a combination of polymorphisms in different genes may affect the immune system and cause a higher basal level of suPAR. Additional isoforms generated by alternative splicing have been described on the RNA level, but whether these are transcribed and their possible roles remain unclear [38]
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