Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor

Dowsett, Joseph; Ferkingstad, Egil; Rasmussen, Line Jee Hartmann; Thørner, Lise Wegner; Magnússon, Magnús K.; Sugden, Karen; Þorleifsson, Guðmar; Frigge, Michael L.; Burgdorf, Kristoffer Sølvsten; Ostrowski, Sisse Rye; Sørensen, Erik; Erikstrup, Christian; Pedersen, Ole Birger; Hansen, Thomas Folkmann; Banasik, Karina; Brunak, Søren; Andersen, Steffen; Jemec, Gregor B.E.; Jennum, Poul; Nielsen, Rene Kasper; Nyegaard, Mette; Paarup, Helene M.; Petersen, Mikkel Steen; Werge, Thomas; Þorsteinsdóttir, Unnur; Tragante, Vinicius; Lund, Sigrún H.; Stefánsdóttir, Lilja; Gunnarson, Bjarni; Poulton, Richie; Arseneault, Louise; Caspi, Avshalom; Moffitt, Terrie E.; Guðbjartsson, Daníel F.; Eugen‐Olsen, Jesper; Stefánsson, Hreinn; Stefánsson, Kāri; Ullum, Henrik

doi:10.1038/s42003-021-02144-8

Cited by 16 publications

(20 citation statements)

References 85 publications

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“…NLRP3, a component of the NLRP3-inflammasome, is also a mediator of neuroinflammation and its dysregulation has been implicated in neurodegeneration ( Ising et al, 2019 ; Pellegrini et al, 2020 ). Plau is a gene related to aging and age-related diseases ( Cardoso et al, 2018 ) and has been suggested to exert chronic inflammatory effects ( Cardoso et al, 2018 ; Dowsett et al, 2021 ). Our integrated pathway analysis showed that neuroinflammation-related pathways ( Walker et al, 2022 ) such as Toll-like receptor signaling pathway, NOD-like receptor signaling pathway, cytokine-cytokine receptor interaction, NF-kB signaling pathways, JAK-STAT signaling pathway, PI3K-Akt signaling pathway, and Sphingolipid signaling pathway were the top-ranked KEGG pathways.…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis reveals neuroinflammation, activated glial signaling, and dysregulated synaptic signaling and metabolism in the hippocampus of aged mice

Xu²,

Lin³

et al. 2022

Front. Aging Neurosci.

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Aging is an intricate biological event that occurs in both vertebrates and invertebrates. During the aging process, the brain, a vulnerable organ, undergoes structural and functional alterations, resulting in behavioral changes. The hippocampus has long been known to be critically associated with cognitive impairment, dementia, and Alzheimer’s disease during aging; however, the underlying mechanisms remain largely unknown. In this study, we hypothesized that altered metabolic and gene expression profiles promote the aging process in the hippocampus. Behavioral tests showed that exploration, locomotion, learning, and memory activities were reduced in aged mice. Metabolomics analysis identified 69 differentially abundant metabolites and showed that the abundance of amino acids, lipids, and microbiota-derived metabolites (MDMs) was significantly altered in hippocampal tissue of aged animals. Furthermore, transcriptomic analysis identified 376 differentially expressed genes in the aged hippocampus. A total of 35 differentially abundant metabolites and 119 differentially expressed genes, constituting the top 200 correlations, were employed for the co-expression network. The multi-omics analysis showed that pathways related to inflammation, microglial activation, synapse, cell death, cellular/tissue homeostasis, and metabolism were dysregulated in the aging hippocampus. Our data revealed that metabolic perturbations and gene expression alterations in the aged hippocampus were possibly linked to their behavioral changes in aged mice; we also provide evidence that altered MDMs might mediate the interaction between gut and brain during the aging process.

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Section: Discussionmentioning

confidence: 99%

Multi-omics analysis reveals neuroinflammation, activated glial signaling, and dysregulated synaptic signaling and metabolism in the hippocampus of aged mice

Xu²,

Lin³

et al. 2022

Front. Aging Neurosci.

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“…In addition to adaptable contributions by lifestyle, underlying chronic disease, and acute conditions, genetic predispositions also affect an individual’s tissue uPAR expression and blood suPAR level. 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 genome-wide significant sequence variants associated with suPAR across 11 distinct loci. 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 kidney-disease-associated gene PLA2R1 , and genes with relations to glycosylation, glycoprotein biosynthesis, and the immune response ( 30 ).…”

Section: Introductionmentioning

confidence: 99%

“…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 genome-wide significant sequence variants associated with suPAR across 11 distinct loci. 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 kidney-disease-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.…”

Section: Introductionmentioning

confidence: 99%

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

2021

Self Cite

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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.

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“…Elevated plasmin and plasminogen levels are common findings in severe COVID-19 illness as well as in patients with various chronic diseases, including hypertension, diabetes, and cardiovascular diseases. This may account for an unfavorable COVID-19 prognosis in patients with these disorders [214,215]. Moreover, SARS-CoV-2 may benefit from its association with Mycoplasma as this bacterium can directly block host immunoglobulins, protecting the virus [216,217].…”

Section: Rethinking Mycoplasmamentioning

confidence: 99%

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

Sfera

Osorio

Hazan³

et al. 2022

Endocrines

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Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.

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Eleven genomic loci affect plasma levels of chronic inflammation marker soluble urokinase-type plasminogen activator receptor

Cited by 16 publications

References 85 publications

Multi-omics analysis reveals neuroinflammation, activated glial signaling, and dysregulated synaptic signaling and metabolism in the hippocampus of aged mice

Multi-omics analysis reveals neuroinflammation, activated glial signaling, and dysregulated synaptic signaling and metabolism in the hippocampus of aged mice

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

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

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