Publications by authors named "Claude Libert"

199 Publications

Bidirectional Crosstalk Between Hypoxia Inducible Factors and Glucocorticoid Signalling in Health and Disease.

Front Immunol 2021 4;12:684085. Epub 2021 Jun 4.

Centre for Inflammation Research, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.

Glucocorticoid-induced (GC) and hypoxia-induced transcriptional responses play an important role in tissue homeostasis and in the regulation of cellular responses to stress and inflammation. Evidence exists that there is an important crosstalk between both GC and hypoxia effects. Hypoxia is a pathophysiological condition to which cells respond quickly in order to prevent metabolic shutdown and death. The hypoxia inducible factors (HIFs) are the master regulators of oxygen homeostasis and are responsible for the ability of cells to cope with low oxygen levels. Maladaptive responses of HIFs contribute to a variety of pathological conditions including acute mountain sickness (AMS), inflammation and neonatal hypoxia-induced brain injury. Synthetic GCs which are analogous to the naturally occurring steroid hormones (cortisol in humans, corticosterone in rodents), have been used for decades as anti-inflammatory drugs for treating pathological conditions which are linked to hypoxia (i.e. asthma, ischemic injury). In this review, we investigate the crosstalk between the glucocorticoid receptor (GR), and HIFs. We discuss possible mechanisms by which GR and HIF influence one another, and , and the therapeutic effects of GCs on HIF-mediated diseases.
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http://dx.doi.org/10.3389/fimmu.2021.684085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211996PMC
June 2021

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.

Sci Adv 2021 May 7;7(19). Epub 2021 May 7.

Laboratory of Tumor Inflammation and Angiogenesis, CCB, VIB, Leuven, Belgium.

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.
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http://dx.doi.org/10.1126/sciadv.abf0466DOI Listing
May 2021

Ratpost: a searchable database of protein-inactivating sequence variations in 40 sequenced rat-inbred strains.

Mamm Genome 2021 02 22;32(1):1-11. Epub 2021 Jan 22.

VIB-UGent Center for Inflammation Research, Ghent, Belgium.

Rat-inbred strains are essential as scientific tools. We have analyzed the publicly available genome sequences of 40 rat-inbred strains and provide an overview of sequence variations leading to amino acid changes in protein-coding genes, premature STOP codons or loss of STOP codons, and short in-frame insertions and deletions of all protein-coding genes across all these inbred lines. We provide an overview of the predicted impact on protein function of all these affected proteins in the database, by comparing their sequence with the sequences of the rat reference strain BN/SsNHsdMcwi. We also investigate the flaws of the protein-coding sequences of this reference strain itself, by comparing them with a consensus genome. These data can be retrieved via a searchable website (Ratpost.be) and allow a global, better interpretation of genetic background effects and a source of naturally defective alleles in these 40 sequenced classical and high-priority rat-inbred strains.
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http://dx.doi.org/10.1007/s00335-020-09853-1DOI Listing
February 2021

Turning a pathogen protein into a therapeutic tool for sepsis.

EMBO Mol Med 2021 Jan 17;13(1):e13589. Epub 2020 Dec 17.

Center for Inflammation Research, VIB, Ghent, Belgium.

Sepsis causes unacceptably high amounts of deaths worldwide. It is a huge unmet medical need, and new therapeutic interventions for sepsis and septic shock are urgently needed. By studying the mechanism by which a bacterial protein undermines the inflammatory function of macrophages, Kim et al, in the last issue of EMBO Molecular Medicine, have developed a new therapeutic protein drug, which appears to have very promising protective activities in a well-validated and aggressive polymicrobial sepsis model in mice. The chimeric protein is thought to limit macrophage inflammation while activating phagocytosis, and so, it hits two macrophage pathways at once.
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http://dx.doi.org/10.15252/emmm.202013589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799353PMC
January 2021

Zinc inhibits lethal inflammatory shock by preventing microbe-induced interferon signature in intestinal epithelium.

EMBO Mol Med 2020 10 11;12(10):e11917. Epub 2020 Sep 11.

Center for Inflammation Research, VIB, Ghent, Belgium.

The cytokine TNF drives inflammatory diseases, e.g., Crohn's disease. In a mouse model of TNF-induced systemic inflammatory response syndrome (SIRS), severe impact on intestinal epithelial cells (IECs) is observed. Zinc confers complete protection in this model. We found that zinc no longer protects in animals which lack glucocorticoids (GCs), or express mutant versions of their receptor GR in IECs, nor in mice which lack gut microbiota. RNA-seq studies in IECs showed that zinc caused reduction in expression of constitutive (STAT1-induced) interferon-stimulated response (ISRE) genes and interferon regulatory factor (IRF) genes. Since some of these genes are involved in TNF-induced cell death in intestinal crypt Paneth cells, and since zinc has direct effects on the composition of the gut microbiota (such as several Staphylococcus species) and on TNF-induced Paneth cell death, we postulate a new zinc-related anti-inflammatory mechanism. Zinc modulates the gut microbiota, causing less induction of ISRE/IRF genes in crypt cells, less TNF-induced necroptosis in Paneth cells, and less fatal evasion of gut bacteria into the system.
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http://dx.doi.org/10.15252/emmm.201911917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539219PMC
October 2020

Glucocorticoids in Sepsis: To Be or Not to Be.

Front Immunol 2020 21;11:1318. Epub 2020 Jul 21.

Center for Inflammation Research, VIB, Ghent, Belgium.

Sepsis is a highly lethal syndrome resulting from dysregulated immune and metabolic responses to infection, thereby compromising host homeostasis. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequently adrenocortical glucocorticoid (GC) production during sepsis are important regulatory processes to maintain homeostasis. Multiple preclinical studies have proven the pivotal role of endogenous GCs in tolerance against sepsis by counteracting several of the sepsis characteristics, such as excessive inflammation, vascular defects, and hypoglycemia. Sepsis is however often complicated by dysfunction of the HPA axis, resulting from critical-illness-related corticosteroid insufficiency (CIRCI) and GC resistance. Therefore, GCs have been tested as an adjunctive therapy in sepsis and septic shock in different randomized clinical trials (RCTs). Nonetheless, these studies produced conflicting results. Interestingly, adding vitamin C and thiamin to GC therapy enhances the effects of GCs, probably by reducing GC resistance, and this results in an impressive reduction in sepsis mortality as was shown in two recent preliminary retrospective before-after studies. Multiple RCTs are currently underway to validate this new combination therapy in sepsis.
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http://dx.doi.org/10.3389/fimmu.2020.01318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396579PMC
April 2021

Glucocorticoids limit lipopolysaccharide-induced lethal inflammation by a double control system.

EMBO Rep 2020 07 8;21(7):e49762. Epub 2020 May 8.

VIB Center for Inflammation Research, Ghent, Belgium.

Lipopolysaccharides (LPS) can lead to a lethal endotoxemia, which is a systemic inflammatory response syndrome (SIRS) characterized by a systemic release of cytokines, such as TNF. Endotoxemia is studied intensely, as a model system of Gram-negative infections. LPS- and TNF-induced SIRS involve a strong induction of interferon-stimulated genes (ISGs), some of which cause cell death in the intestinal epithelium cells (IECs). It is well known that glucocorticoids (GCs) protect against endotoxemia. By applying numerous mutant mouse lines, our data support a model whereby GCs, via their glucocorticoid receptor (GR), apply two key mechanisms to control endotoxemia, (i) at the level of suppression of TNF production in a GR monomer-dependent way in macrophages and (ii) at the level of inhibition of TNFR1-induced ISG gene expression and necroptotic cell death mediators in IECs in a GR dimer-dependent way. Our data add new important insights to the understanding of the role of TNF in endotoxemia and the two separate key roles of GCs in suppressing TNF production and activity.
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http://dx.doi.org/10.15252/embr.201949762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332980PMC
July 2020

Taking the STING Out of Sepsis?

Cell Host Microbe 2020 04;27(4):491-493

Center for Inflammation Research, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address:

In this issue of Cell Host & Microbe, Zhang et al. use a sepsis mouse model to show that macrophage-specific release of coagulation factor F3 depends on pathogen detection and responses mediated by TMEM173/STING. The therapeutic power of targeting TMEM173/STING-F3 is evident in mice, but will it penetrate the sepsis bedside?
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http://dx.doi.org/10.1016/j.chom.2020.03.016DOI Listing
April 2020

GILZ in sepsis: "Poor is the pupil who does not surpass his master".

Eur J Immunol 2020 04 13;50(4):490-493. Epub 2020 Mar 13.

Center for Inflammation Research, VIB, Ghent, Belgium.

With the legendary saying of Leonardo da Vinci in the title, we suggest that Glucocorticoid Induced Leucine Zipper (GILZ) may have more promising effects against polymicrobial sepsis, than glucocorticoids (GC). Indeed, the use of GCs in sepsis remains a matter of debate. The rationale for their use in sepsis is to modulate the exaggerated inflammatory response while maintaining innate immunity. However, GC resistance and side-effects limit their therapeutic value in sepsis. Hence, there is a growing interest in understanding the mechanisms by which GCs modulate immune responses upon infection. In this issue of the European Journal of Immunology, Ellouze et al. provide data demonstrating that deregulated expression of GILZ, a GC-induced protein, in monocytes/macrophages (M/M) recovered from septic shock patients may contribute to the pathogenesis. Furthermore, the authors demonstrate that GILZ overexpression in M/M improves outcome in septic animals by limiting systemic inflammation while increasing bacterial clearance. Overall, these data provide evidence that GCs may modulate immune responses via GILZ and that GILZ is a valuable alternative for GC therapy in sepsis.
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http://dx.doi.org/10.1002/eji.202048582DOI Listing
April 2020

Phytohormones: Multifunctional nutraceuticals against metabolic syndrome and comorbid diseases.

Biochem Pharmacol 2020 05 20;175:113866. Epub 2020 Feb 20.

VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address:

Metabolic syndrome is characterized by the co-occurrence of diverse symptoms initiating the development of type 2 diabetes, cardiovascular diseases, and a variety of comorbid diseases. The complex constellation of numerous comorbidities makes it difficult to develop common therapeutic approaches that ameliorate these pathological features simultaneously. The plant hormones abscisic acid, salicylic acid, auxin, and cytokinins, have shown promising anti-inflammatory and pro-metabolic effects that could mitigate several disorders relevant to metabolic syndrome. Intriguingly, besides plants, human cells and gut microbes also endogenously produce these molecules, indicating a role in the complex interplay between inflammatory responses associated with metabolic syndrome, the gut microbiome, and nutrition. Here, we introduce how bioactive phytohormones can be generated endogenously and through the gut microbiome. These molecules subsequently influence immune responses and metabolism. We also elaborate on how phytohormones can beneficially modulate metabolic syndrome comorbidities, and propose them as nutraceuticals.
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http://dx.doi.org/10.1016/j.bcp.2020.113866DOI Listing
May 2020

Potential of glucocorticoids to treat intestinal inflammation during sepsis.

Curr Opin Pharmacol 2020 08 25;53:1-7. Epub 2020 Jan 25.

VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address:

Glucocorticoids (GCs) are steroid hormones characterized by their anti-inflammatory and immunosuppressive nature. Although GCs are very commonly prescribed, in several diseases, including sepsis, their clinical treatment is hampered by side effects and by the occurrence of glucocorticoid resistance (GCR). Sepsis is defined as a life-threatening organ dysfunction, initiated by a dysregulated systemic host response to infections. With at least 19 million cases per year and a lethality rate of about 25%, sepsis is one of the most urgent unmet medical needs. The gut is critically affected during sepsis and is considered as a driving force in this disease. Despite there is no effective treatment for sepsis, pre-clinical studies show promising results by preserving or restoring gut integrity. Since GC treatment reveals therapeutic effects in Crohn's disease (CD) and in pre-clinical sepsis models, we hypothesize that targeting GCs to the gut or stimulating local GC production in the gut forms an interesting strategy for sepsis treatment. According to recent findings that show that dimerization of the glucocorticoid receptor (GR) is essential in inducing anti-inflammatory effects in pre-clinical sepsis models, we predict that new generation GCs that selectively dimerize the GR, can therefore positively affect the outcome of sepsis treatment.
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http://dx.doi.org/10.1016/j.coph.2019.12.005DOI Listing
August 2020

Hypoxia-inducible factors in metabolic reprogramming during sepsis.

FEBS J 2020 04 3;287(8):1478-1495. Epub 2020 Feb 3.

Center for Inflammation Research, VIB, Ghent, Belgium.

Sepsis is a highly heterogeneous syndrome that is caused by an imbalanced host response to infection. Despite huge investments, sepsis remains a contemporary threat with significant burden on health systems. Vascular dysfunction and elevated oxygen consumption by highly metabolically active immune cells result in tissue hypoxia during inflammation. The transcription factor hypoxia-inducible factor-1a (HIF1α), and its family members, plays an important role in cellular metabolism and adaptation to cellular stress caused by hypoxia. In this review, we discuss the role of HIF in sepsis. We show possible mechanisms by which the inflammatory response activated during sepsis affects the HIF pathway. The activated HIF pathway in turn changes the metabolism of both innate and adaptive immune cells. As HIF expression in leukocytes of septic patients can be directly linked with mortality, we discuss multiple ways of interfering with the HIF signaling pathway.
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http://dx.doi.org/10.1111/febs.15222DOI Listing
April 2020

Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis.

EMBO Mol Med 2020 02 9;12(2):e11319. Epub 2020 Jan 9.

Center for Inflammation Research, VIB, Ghent, Belgium.

Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease; however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARα is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARα in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARα levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARα agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARα function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point toward new therapeutic leads in sepsis.
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http://dx.doi.org/10.15252/emmm.201911319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005534PMC
February 2020

Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization.

PLoS One 2019 23;14(12):e0226753. Epub 2019 Dec 23.

Center for Inflammation Research, VIB, Ghent, Belgium.

Stress is a major risk factor for depression and anxiety. One of the effects of stress is the (over-) activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of stress hormones such as glucocorticoids (GCs). Chronically increased stress hormone levels have been shown to have detrimental effects on neuronal networks by inhibiting neurotrophic processes particularly in the hippocampus proper. Centrally, GCs modulate metabolic as well as behavioural processes by activating two classes of corticoid receptors, high-affinity mineralocorticoid receptors (MR) and low-affinity glucocorticoid receptors (GR). Upon activation, GR can modulate gene transcription either as a monomeric protein, or as a dimer interacting directly with DNA. GR can also modulate cellular processes via non-genomic mechanisms, for example via a GPCR-protein interaction. We evaluated the behavioral phenotype in mice with a targeted mutation in the GR in a FVB/NJ background. In GRdim/dim mice, GR proteins form poor homodimers, while the GR monomer remains intact. We evaluated the effect of poor GR dimerization on hippocampus-dependent cognition as well as on exploration and emotional behavior under baseline and chronically increased stress hormone levels. We found that GRdim/dim mice did not behave differently from GRwt/wt littermates under baseline conditions. However, after chronic elevation of stress hormone levels, GRdim/dim mice displayed a significant impairment in hippocampus-dependent memory compared to GRwt/wt mice, which correlated with differential expression of hippocampal Bdnf/TrkB and Fkbp5.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226753PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927629PMC
April 2020

A Study of Cecal Ligation and Puncture-Induced Sepsis in Tissue-Specific Tumor Necrosis Factor Receptor 1-Deficient Mice.

Front Immunol 2019 8;10:2574. Epub 2019 Nov 8.

VIB Center for Inflammation Research, Ghent, Belgium.

Sepsis is a complex syndrome resulting from a dysregulated immune response to an infection. Due to the high prevalence, morbidity, and mortality, there is a lot of interest in understanding pathways that play a role in sepsis, with a focus on the immune system. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine and a master regulator of the immune system but clinical trials with TNF blockers in sepsis have failed to demonstrate significant protection. Since TNF stimulates two different receptors, TNF receptor 1 (TNFR1) and TNFR2, pan-TNF inhibition might be suboptimal since both receptors have opposite functions in polymicrobial sepsis. Therefore, we hypothesized that TNF has a dual role in sepsis, namely a mediating and a protective role, and that protection might be obtained by TNFR1-specific inhibition. We here confirmed that TNFR1 mice are protected in the sterile endotoxemia model, whereas TNFR1 deficiency did not protect in the cecal ligation and puncture (CLP)-induced polymicrobial sepsis model. Since whole body TNFR1 blockage might be deleterious because of the antibacterial function of TNF/TNFR1 signaling, we focused on the potential devastating role of TNF/TNFR1 signaling in specific cell types. We were interested in the gut epithelium, the endothelium, and hepatocytes using conditional TNFR1 mice, as these cell types have been shown to play a role in sepsis. However, none of these conditional knockout mice showed improved survival in the CLP model. We conclude that cell-specific targeting of TNFR1 to these cell types has no therapeutic future in septic peritonitis.
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http://dx.doi.org/10.3389/fimmu.2019.02574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856143PMC
October 2020

An extracellular microRNA can rescue lives in sepsis.

EMBO Rep 2020 01 14;21(1):e49193. Epub 2019 Nov 14.

Center for Inflammation Research, VIB, Ghent, Belgium.

Sepsis, or blood poisoning, is a savage response of the body to infection. It can lead to organ failure, blood pressure decline, heart failure, and coma. Between 20 and 30 million people suffer from sepsis each year, leading to 8 million deaths. Although certain people are more at risk than others (young children, elderly), anyone can develop sepsis. Patients are resuscitated and treated with antibiotics, and their organ functions are supported. Despite the investment in sepsis research during the previous decades, successful clinical trials are scarce and sepsis remains one of the most difficult and deadly unmet medical needs of today. A study in this issue now provides new insight into sepsis and points to a therapeutic future [ ].
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http://dx.doi.org/10.15252/embr.201949193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944901PMC
January 2020

Mechanisms Underlying the Functional Cooperation Between PPARα and GRα to Attenuate Inflammatory Responses.

Front Immunol 2019 9;10:1769. Epub 2019 Aug 9.

Translational Nuclear Receptor Research Lab, Ghent, Belgium.

Glucocorticoids (GCs) act via the glucocorticoid receptor (NR3C1, GRα) to combat overshooting responses to infectious stimuli, including lipopolysaccharide (LPS). As such, GCs inhibit the activity of downstream effector cytokines, such as tumor necrosis factor (TNF). PPARα (NR1C1) is a nuclear receptor described to function on the crossroad between lipid metabolism and control of inflammation. In the current work, we have investigated the molecular mechanism by which GCs and PPARα agonists cooperate to jointly inhibit NF-κB-driven expression in A549 cells. We discovered a nuclear mechanism that predominantly targets Mitogen- and Stress-activated protein Kinase-1 activation upon co-triggering GRα and PPARα. GST-pull down data further support that the anti-inflammatory mechanism may additionally involve a non-competitive physical interaction between the p65 subunit of NF-κB, GRα, and PPARα. Finally, to study metabolic effector target cells common to both receptors, we overlaid the effect of GRα and PPARα crosstalk in mouse primary hepatocytes under LPS-induced inflammatory conditions on a genome-wide level. RNA-seq results revealed lipid metabolism genes that were upregulated and inflammatory genes that were additively downregulated. Validation at the cytokine protein level finally supported a consistent additive anti-inflammatory response in hepatocytes.
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http://dx.doi.org/10.3389/fimmu.2019.01769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695567PMC
October 2020

A General Introduction to Glucocorticoid Biology.

Front Immunol 2019 4;10:1545. Epub 2019 Jul 4.

Center for Inflammation Research, VIB, Ghent, Belgium.

Glucocorticoids (GCs) are steroid hormones widely used for the treatment of inflammation, autoimmune diseases, and cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors. Despite their success, GCs are hindered by the occurrence of side effects and glucocorticoid resistance (GCR). Increased knowledge on GC and GR biology together with a better understanding of the molecular mechanisms underlying the GC side effects and GCR are necessary for improved GC therapy development. We here provide a general overview on the current insights in GC biology with a focus on GC synthesis, regulation and physiology, role in inflammation inhibition, and on GR function and plasticity. Furthermore, novel and selective therapeutic strategies are proposed based on recently recognized distinct molecular mechanisms of the GR. We will explain the SEDIGRAM concept, which was launched based on our research results.
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http://dx.doi.org/10.3389/fimmu.2019.01545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621919PMC
October 2020

TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile.

Proc Natl Acad Sci U S A 2019 06 10;116(26):12942-12951. Epub 2019 Jun 10.

Mouse Genetics in Inflammation, VIB Center for Inflammation Research, 9052 Ghent, Belgium;

Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the therapeutic effects, including the antiinflammatory ones of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a problem in the management of inflammatory diseases and can be congenital as well as acquired. The strong proinflammatory cytokine TNF-alpha (TNF) induces an acute form of GCR, not only in mice, but also in several cell lines: e.g., in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-stimulated direct GR-dependent gene up- and down-regulation. We report that TNF has a significant and broad impact on this transcriptional performance of GR, but no impact on nuclear translocation, dimerization, or DNA binding capacity of GR. Proteome-wide proximity-mapping (BioID), however, revealed that the GR interactome was strongly modulated by TNF. One GR cofactor that interacted significantly less with the receptor under GCR conditions is p300. NFκB activation and p300 knockdown both reduced direct transcriptional output of GR whereas p300 overexpression and NFκB inhibition reverted TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis was supported by FRET studies. This mechanism of GCR opens avenues for therapeutic interventions in GCR diseases.
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http://dx.doi.org/10.1073/pnas.1821565116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600915PMC
June 2019

The Response to the Letter to the Editor Titled: "Is Triple Self-plagiarism "OK" If Only Made Transparent?" by Volker R Jacobs, MD, MBA.

Shock 2019 01;51(1):140-141

Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Vienna, Austria University of California School of Medicine, San Francisco, California Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany Center for Inflammation Research, VIB, University Ghent, Ghent, Belgium Boston University School of Medicine, Boston, Massachusetts The William Harvey Research Institute, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, Ohio.

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http://dx.doi.org/10.1097/SHK.0000000000001294DOI Listing
January 2019

Should we target TNF receptors in the intestinal epithelium with glucocorticoids during systemic inflammation?

Expert Opin Ther Targets 2018 12 23;22(12):1029-1037. Epub 2018 Oct 23.

a VIB Center for Inflammation Research , Ghent , Belgium.

Introduction: Reverting Systemic inflammatory response syndromes (SIRS), particularly sepsis, is a huge challenge of contemporary medicine. Inhibition of the cytokine tumor necrosis factor alpha (TNFα), originally considered as a mediator in sepsis, has led to frustrating results. Equally so, glucocorticoids (GCs), renowned for their role in numerous inflammatory diseases, remain controversial in sepsis. Areas covered: We discuss how, in SIRS, the intestinal epithelium is a critical TNF-responsive target. Inhibition of TNF receptor 1 (TNFR1), rather than TNF, may be a more targeted and safe therapeutic approach. In intestinal epithelial cells (IECs), a strong interplay between GCs and TNF exists. Addressing GCs in these cells is crucial in SIRS and sepsis and would avoid dose-limiting off-target effects, for example on immune cells and phagocytes. Expert opinion: The targeting of TNFR1 specifically at the level of IECs, potentially combined with IEC-specific stimulation of GR, could lead to a more safe and targeted treatment for SIRS and sepsis.
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http://dx.doi.org/10.1080/14728222.2018.1539078DOI Listing
December 2018

Do people living with HIV experience greater age advancement than their HIV-negative counterparts?

AIDS 2019 02;33(2):259-268

Department of Global Health, Academic Medical Center and Amsterdam Institute for Global Health and Development.

Objectives: Despite successful antiretroviral therapy, people living with HIV (PLWH) may show signs of premature/accentuated aging. We compared established biomarkers of aging in PLWH, appropriately chosen HIV-negative individuals, and blood donors, and explored factors associated with biological age advancement.

Design: Cross-sectional analysis of 134 PLWH on suppressive antiretroviral therapy, 79 lifestyle-comparable HIV-negative controls aged 45 years or older from the Co-morBidity in Relation to AIDS (COBRA) cohort, and 35 age-matched blood donors.

Methods: Biological age was estimated using a validated algorithm based on 10 biomarkers. Associations between 'age advancement' (biological minus chronological age) and HIV status/parameters, lifestyle, cytomegalovirus (CMV), hepatitis B (HBV) and hepatitis C virus (HCV) infections were investigated using linear regression.

Results: The average (95% CI) age advancement was greater in both HIV-positive [13.2 (11.6-14.9) years] and HIV-negative [5.5 (3.8-7.2) years] COBRA participants compared with blood donors [-7.0 (-4.1 to -9.9) years, both P's < 0.001)], but also in HIV-positive compared with HIV-negative participants (P < 0.001). Chronic HBV, higher anti-CMV IgG titer and CD8 T-cell count were each associated with increased age advancement, independently of HIV-status/group. Among HIV-positive participants, age advancement was increased by 3.5 (0.1-6.8) years among those with nadir CD4+ T-cell count less than 200 cells/μl and by 0.1 (0.06-0.2) years for each additional month of exposure to saquinavir.

Conclusion: Both treated PLWH and lifestyle-comparable HIV-negative individuals show signs of age advancement compared with blood donors, to which persistent CMV, HBV co-infection and CD8+ T-cell activation may have contributed. Age advancement remained greatest in PLWH and was related to prior immunodeficiency and cumulative saquinavir exposure.
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http://dx.doi.org/10.1097/QAD.0000000000002063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319574PMC
February 2019

Easy Access to and Applications of the Sequences of All Protein-Coding Genes of All Sequenced Mouse Strains.

Trends Genet 2018 12 19;34(12):899-902. Epub 2018 Sep 19.

Vlaams Instituut voor Biotechnologie (VIB) Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address:

An easily accessible and searchable overview of all protein sequences in the 36 genome-sequenced mouse strains, compared to those in the reference strain C57BL/6J, is now available, as well as an overview of the aberrant proteins in this reference strain. We provide an insight into the advantages of using these databases.
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http://dx.doi.org/10.1016/j.tig.2018.08.007DOI Listing
December 2018

The autophagy receptor SQSTM1/p62 mediates anti-inflammatory actions of the selective NR3C1/glucocorticoid receptor modulator compound A (CpdA) in macrophages.

Autophagy 2018 14;14(12):2049-2064. Epub 2018 Sep 14.

a Receptor Research Laboratories, Nuclear Receptor Lab , Ghent University , Ghent , Belgium.

Glucocorticoids are widely used to treat inflammatory disorders; however, prolonged use of glucocorticoids results in side effects including osteoporosis, diabetes and obesity. Compound A (CpdA), identified as a selective NR3C1/glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1) modulator, exhibits an inflammation-suppressive effect, largely in the absence of detrimental side effects. To understand the mechanistic differences between the classic glucocorticoid dexamethasone (DEX) and CpdA, we looked for proteins oppositely regulated in bone marrow-derived macrophages using an unbiased proteomics approach. We found that the autophagy receptor SQSTM1 but not NR3C1 mediates the anti-inflammatory action of CpdA. CpdA drives SQSTM1 upregulation by recruiting the NFE2L2 transcription factor to its promoter. In contrast, the classic NR3C1 ligand dexamethasone recruits NR3C1 to the Sqstm1 promoter and other NFE2L2-controlled gene promoters, resulting in gene downregulation. Both DEX and CpdA induce autophagy, with marked different autophagy characteristics and morphology. Suppression of LPS-induced Il6 and Ccl2 genes by CpdA in macrophages is hampered upon Sqstm1 silencing, confirming that SQSTM1 is essential for the anti-inflammatory capacity of CpdA, at least in this cell type. Together, these results demonstrate how off-target mechanisms of selective NR3C1 ligands may contribute to a more efficient anti-inflammatory therapy.
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http://dx.doi.org/10.1080/15548627.2018.1495681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984772PMC
October 2019

A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation.

Sci Rep 2018 08 27;8(1):12894. Epub 2018 Aug 27.

Center for Inflammation Research, VIB, Ghent, Belgium.

It has been suggested that glucocorticoid receptor (GR) agonists that promote GR homodimerization more than standard glucocorticoids such as Dexamethasone could be more effective anti-inflammatory molecules against acute and life-threatening inflammatory conditions. To test this hypothesis, we set up a screening pipeline aimed at discovering such Selective Dimerizing GR Agonists and Modulators (SEDIGRAM). The pipeline consists of a reporter gene assay based on a palindromic glucocorticoid responsive element (GRE). This assay represents GR dimerization in human A549 lung epithelial cells. In the pipeline, this is followed by analysis of endogenous GRE-driven gene expression, a FRET assay confirming dimerization, and monitoring of in vitro and in vivo anti-inflammatory activity. In a proof of principle experiment, starting from seven candidate compounds, we identified two potentially interesting compounds (Cortivazol and AZD2906) that confer strong protection in a mouse model of aggressive TNF-induced lethal inflammation. A screening pipeline for SEDIGRAM may assist the search for compounds that promote GR dimerization and limit overwhelming acute inflammatory responses.
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http://dx.doi.org/10.1038/s41598-018-31150-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110732PMC
August 2018

Overexpression of Gilz Protects Mice Against Lethal Septic Peritonitis.

Shock 2019 08;52(2):208-214

VIB Center for Inflammation Research, Ghent, Belgium.

Sepsis in humans and experimental animals is characterized by an acute inflammatory response. glucocorticoids (GCs) are widely used for the treatment of many inflammatory disorders, yet their effectiveness in sepsis is debatable. One of the major anti-inflammatory proteins induced by GCs is glucocorticoid-induced leucine zipper (GILZ, coded by the TSC22D3 gene). We found that TSC22D3 mRNA expression is downregulated in white blood cells of human sepsis patients. Interestingly, transgenic GILZ-overexpressing mice (GILZ-tg) showed better survival rates in the cecal ligation and puncture (CLP) model of mouse sepsis. To our surprise, GILZ had only mild anti-inflammatory effects in this model, as the systemic proinflammatory response was not significantly reduced in GILZ-tg mice compared with control mice. During CLP, we observed reduced bacterial counts in blood of GILZ-tg mice compared with control mice. We found increased expression of Tsc22d3 mRNA specifically in peritoneal exudate cells in the CLP model, as well as increased capacity for bacterial phagocytosis of CD45 GILZ-tg cells compared with CD45 GILZ-wt cells. Hence, we believe that the protective effects of GILZ in the CLP model can be linked to a more efficient phagocytosis.
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http://dx.doi.org/10.1097/SHK.0000000000001252DOI Listing
August 2019

Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis.

Intensive Care Med Exp 2018 Aug 14;6(1):26. Epub 2018 Aug 14.

Xiangya School of Medicine, Central South University, Chagnsha, Hunan, China.

Background: Pre-clinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of pre-clinical models of sepsis has not been done and clear modeling guidelines are lacking.

Objective: To address this deficit, a Wiggers-Bernard Conference on pre-clinical sepsis modeling was held in Vienna in May 2017. The goal of the conference was to identify limitations of pre-clinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Pre-Clinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models.

Methods: A total of 31 experts from 13 countries participated and were divided into 6 thematic working groups (WG): (1) study design, (2) humane modeling, (3) infection types, (4) organ failure/dysfunction, (5) fluid resuscitation, and (6) antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013).

Results: Overall, the participants reached consensus on 29 points; 20 at "recommendation" (R) and 9 at "consideration" (C) strength. This executive summary provides a synopsis of the MQTiPSS consensus (Tables 1, 2, and 3). Detailed commentaries to all Rs and Cs are simultaneously published in three separate full-length papers.

Conclusions: We believe that these recommendations and considerations will serve to bring a level of standardization to pre-clinical models of sepsis and ultimately improve translation of pre-clinical findings. These guideline points are proposed as "best practices" for animal models of sepsis that should be implemented. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection and Intensive Care Medicine Experimental.
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http://dx.doi.org/10.1186/s40635-018-0189-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093828PMC
August 2018

Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): An International Expert Consensus Initiative for Improvement of Animal Modeling in Sepsis.

Shock 2018 10;50(4):377-380

Xiangya School of Medicine, Central South University, Chagnsha, Hunan, China.

Preclinical animal studies precede the majority of clinical trials. While the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review of preclinical models of sepsis has not been done and clear modeling guidelines are lacking. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling was held in Vienna in May, 2017. The goal of the conference was to identify limitations of preclinical sepsis models and to propose a set of guidelines, defined as the "Minimum Quality Threshold in Preclinical Sepsis Studies" (MQTiPSS), to enhance translational value of these models. A total of 31 experts from 13 countries participated and were divided into six thematic Working Groups: Study Design, Humane modeling, Infection types, Organ failure/dysfunction, Fluid resuscitation, and Antimicrobial therapy endpoints. As basis for the MQTiPSS discussions, the participants conducted a literature review of the 260 most highly cited scientific articles on sepsis models (2002-2013). Overall, the participants reached consensus on 29 points; 20 at "recommendation" and nine at "consideration" strength. This Executive Summary provides a synopsis of the MQTiPSS consensus. We believe that these recommendations and considerations will serve to bring a level of standardization to preclinical models of sepsis and ultimately improve translation of preclinical findings. These guideline points are proposed as "best practices" for animal models of sepsis that should be implemented. To encourage its wide dissemination, this article is freely accessible on the Intensive Care Medicine Experimental and Infection journal websites. In order to encourage its wide dissemination, this article is freely accessible in Shock, Infection, and Intensive Care Medicine Experimental.
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http://dx.doi.org/10.1097/SHK.0000000000001212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133201PMC
October 2018

Part II: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Types of Infections and Organ Dysfunction Endpoints.

Shock 2019 01;51(1):23-32

Boston University School of Medicine, Boston, Massachusetts.

Although the clinical definitions of sepsis and recommended treatments are regularly updated, a systematic review has not been done for preclinical models. To address this deficit, a Wiggers-Bernard Conference on preclinical sepsis modeling reviewed the 260 most highly cited papers between 2003 and 2012 using sepsis models to create a series of recommendations. This Part II report provides recommendations for the types of infections and documentation of organ injury in preclinical sepsis models. Concerning the types of infections, the review showed that the cecal ligation and puncture model was used for 44% of the studies while 40% injected endotoxin. Recommendation #8 (numbered sequentially from Part I): endotoxin injection should not be considered as a model of sepsis; live bacteria or fungal strains derived from clinical isolates are more appropriate. Recommendation #9: microorganisms should replicate those typically found in human sepsis. Sepsis-3 states that sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection, but the review of the papers showed limited attempts to document organ dysfunction. Recommendation #10: organ dysfunction definitions should be used in preclinical models. Recommendation #11: not all activities in an organ/system need to be abnormal to verify organ dysfunction. Recommendation #12: organ dysfunction should be measured in an objective manner using reproducible scoring systems. Recommendation #13: not all experiments must measure all parameters of organ dysfunction, but investigators should attempt to fully capture as much information as possible. These recommendations are proposed as "best practices" for animal models of sepsis.
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http://dx.doi.org/10.1097/SHK.0000000000001242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296883PMC
January 2019