539 results on '"Libert C"'
Search Results
152. Point mutation I634A in the glucocorticoid receptor causes embryonic lethality by reduced ligand binding.
- Author
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Timmermans S, Verhoog NJD, Van Looveren K, Dewaele S, Hochepied T, Eggermont M, Gilbert B, Boerema-de Munck A, Vanderhaeghen T, Vanden Berghe J, Garcia Gonzalez N, Vandewalle J, Bloch Y, Provost M, Savvides SN, De Bosscher K, Declercq W, Rottier RJ, Louw A, and Libert C
- Subjects
- Animals, Glucocorticoids pharmacology, Ligands, Mice, Dexamethasone pharmacology, Point Mutation, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism
- Abstract
The glucocorticoid (GC) receptor (GR) is essential for normal development and in the initiation of inflammation. Healthy GR
dim/dim mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA-binding domain (DBD) (here GRD/D ) have previously helped to define the functions of GR monomers and dimers. Since GRD/D retains residual dimerization capacity, here we generated the dimer-nullifying double mutant GRD+L/D+L mice, featuring an additional mutation (I634A) in the ligand-binding domain (LBD) of GR. These mice are perinatally lethal, as are GRL/L mice (these mice have the I634A mutation but not the A465T mutation), displaying improper lung and skin formation. Using embryonic fibroblasts, high and low doses of dexamethasone (Dex), nuclear translocation assays, RNAseq, dimerization assays, and ligand-binding assays (and Kd values), we found that the lethal phenotype in these mice is due to insufficient ligand binding. These data suggest there is some correlation between GR dimerization potential and ligand affinity. We conclude that even a mutation as subtle as I634A, at a position not directly involved in ligand interactions sensu stricto, can still influence ligand binding and have a lethal outcome., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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153. Reprogramming of glucocorticoid receptor function by hypoxia.
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Vanderhaeghen T, Timmermans S, Watts D, Paakinaho V, Eggermont M, Vandewalle J, Wallaeys C, Van Wyngene L, Van Looveren K, Nuyttens L, Dewaele S, Vanden Berghe J, Lemeire K, De Backer J, Dirkx L, Vanden Berghe W, Caljon G, Ghesquière B, De Bosscher K, Wielockx B, Palvimo JJ, Beyaert R, and Libert C
- Subjects
- Animals, Dexamethasone metabolism, Dexamethasone pharmacology, Humans, Hypothalamo-Hypophyseal System metabolism, Hypoxia genetics, Hypoxia metabolism, Mice, Pituitary-Adrenal System metabolism, Glucocorticoids metabolism, Glucocorticoids pharmacology, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism
- Abstract
Here, we investigate the impact of hypoxia on the hepatic response of glucocorticoid receptor (GR) to dexamethasone (DEX) in mice via RNA-sequencing. Hypoxia causes three types of reprogramming of GR: (i) much weaker induction of classical GR-responsive genes by DEX in hypoxia, (ii) a number of genes is induced by DEX specifically in hypoxia, and (iii) hypoxia induces a group of genes via activation of the hypothalamic-pituitary-adrenal (HPA) axis. Transcriptional profiles are reflected by changed GR DNA-binding as measured by ChIP sequencing. The HPA axis is induced by hypothalamic HIF1α and HIF2α activation and leads to GR-dependent lipolysis and ketogenesis. Acute inflammation, induced by lipopolysaccharide, is prevented by DEX in normoxia but not during hypoxia, and this is attributed to HPA axis activation by hypoxia. We unfold new physiological pathways that have consequences for patients suffering from GC resistance., (© 2021 The Authors.)
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- 2022
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154. miR-511 Deficiency Protects Mice from Experimental Colitis by Reducing TLR3 and TLR4 Responses via WD Repeat and FYVE-Domain-Containing Protein 1.
- Author
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Rahman S, Vandewalle J, van Hamersveld PHP, Verseijden C, Welting O, Jongejan A, Casanova P, Meijer SL, Libert C, Hakvoort TBM, de Jonge WJ, and Heinsbroek SEM
- Subjects
- Animals, Colitis chemically induced, Colitis microbiology, Colitis pathology, Colon pathology, Dextran Sulfate, Female, Gene Expression Regulation, Inflammation genetics, Inflammation pathology, Lipopolysaccharides, Macrophages metabolism, Macrophages microbiology, Male, Mice, Inbred C57BL, MicroRNAs genetics, Monocytes metabolism, Mice, Adaptor Proteins, Signal Transducing metabolism, Colitis genetics, MicroRNAs metabolism, Toll-Like Receptor 3 metabolism, Toll-Like Receptor 4 metabolism
- Abstract
Antimicrobial responses play an important role in maintaining intestinal heath. Recently we reported that miR-511 may regulate TLR4 responses leading to enhanced intestinal inflammation. However, the exact mechanism remained unclear. In this study we investigated the effect of miR-511 deficiency on anti-microbial responses and DSS-induced intestinal inflammation. miR-511-deficient mice were protected from DSS-induced colitis as shown by significantly lower disease activity index, weight loss and histology scores in the miR-511-deficient group. Furthermore, reduced inflammatory cytokine responses were observed in colons of miR-511 deficient mice. In vitro studies with bone marrow-derived M2 macrophages showed reduced TLR3 and TLR4 responses in miR-511-deficient macrophages compared to WT macrophages. Subsequent RNA sequencing revealed Wdfy1 as the potential miR-511 target. WDFY1 deficiency is related to impaired TLR3/TLR4 immune responses and the expression was downregulated in miR-511-deficient macrophages and colons. Together, this study shows that miR-511 is involved in the regulation of intestinal inflammation through downstream regulation of TLR3 and TLR4 responses via Wdfy1.
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- 2021
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155. The androgen receptor depends on ligand-binding domain dimerization for transcriptional activation.
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El Kharraz S, Dubois V, van Royen ME, Houtsmuller AB, Pavlova E, Atanassova N, Nguyen T, Voet A, Eerlings R, Handle F, Prekovic S, Smeets E, Moris L, Devlies W, Ohlsson C, Poutanen M, Verstrepen KJ, Carmeliet G, Launonen KM, Helminen L, Palvimo JJ, Libert C, Vanderschueren D, Helsen C, and Claessens F
- Subjects
- Animals, Binding Sites genetics, Dimerization, Ligands, Male, Mice, Transcriptional Activation, Receptors, Androgen chemistry, Receptors, Androgen genetics, Receptors, Androgen metabolism
- Abstract
Whereas dimerization of the DNA-binding domain of the androgen receptor (AR) plays an evident role in recognizing bipartite response elements, the contribution of the dimerization of the ligand-binding domain (LBD) to the correct functioning of the AR remains unclear. Here, we describe a mouse model with disrupted dimerization of the AR LBD (AR
Lmon/Y ). The disruptive effect of the mutation is demonstrated by the feminized phenotype, absence of male accessory sex glands, and strongly affected spermatogenesis, despite high circulating levels of testosterone. Testosterone replacement studies in orchidectomized mice demonstrate that androgen-regulated transcriptomes in ARLmon/Y mice are completely lost. The mutated AR still translocates to the nucleus and binds chromatin, but does not bind to specific AR binding sites. In vitro studies reveal that the mutation in the LBD dimer interface also affects other AR functions such as DNA binding, ligand binding, and co-regulator binding. In conclusion, LBD dimerization is crucial for the development of AR-dependent tissues through its role in transcriptional regulation in vivo. Our findings identify AR LBD dimerization as a possible target for AR inhibition., (© 2021 The Authors.)- Published
- 2021
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156. Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis.
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Vandewalle J, Timmermans S, Paakinaho V, Vancraeynest L, Dewyse L, Vanderhaeghen T, Wallaeys C, Van Wyngene L, Van Looveren K, Nuyttens L, Eggermont M, Dewaele S, Velho TR, Moita LF, Weis S, Sponholz C, van Grunsven LA, Dewerchin M, Carmeliet P, De Bosscher K, Van de Voorde J, Palvimo JJ, and Libert C
- Subjects
- Animals, Glucocorticoids, Lactic Acid, Mice, Receptors, Glucocorticoid metabolism, Vascular Endothelial Growth Factor A, Hyperlactatemia, Sepsis complications, Sepsis metabolism
- Abstract
Sepsis is a potentially lethal syndrome resulting from a maladaptive response to infection. Upon infection, glucocorticoids are produced as a part of the compensatory response to tolerate sepsis. This tolerance is, however, mitigated in sepsis due to a quickly induced glucocorticoid resistance at the level of the glucocorticoid receptor. Here, we show that defects in the glucocorticoid receptor signaling pathway aggravate sepsis pathophysiology by lowering lactate clearance and sensitizing mice to lactate-induced toxicity. The latter is exerted via an uncontrolled production of vascular endothelial growth factor, resulting in vascular leakage and collapse with severe hypotension, organ damage, and death, all being typical features of a lethal form of sepsis. In conclusion, sepsis leads to glucocorticoid receptor failure and hyperlactatemia, which collectively leads to a lethal vascular collapse., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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157. Ecotoxicological risk assessment of contaminants of emerging concern identified by "suspect screening" from urban wastewater treatment plant effluents at a territorial scale.
- Author
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Gosset A, Wiest L, Fildier A, Libert C, Giroud B, Hammada M, Hervé M, Sibeud E, Vulliet E, Polomé P, and Perrodin Y
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- Environmental Monitoring, Risk Assessment, Waste Disposal, Fluid, Wastewater analysis, Water Pollutants, Chemical analysis, Water Pollutants, Chemical toxicity, Water Purification
- Abstract
Urban wastewater treatment plants (WWTP) are a major vector of highly ecotoxic contaminants of emerging concern (CECs) for urban and sub-urban streams. Ecotoxicological risk assessments (ERAs) provide essential information to public environmental authorities. Nevertheless, ERAs are mainly performed at very local scale (one or few WWTPs) and on pre-selected list of CECs. To cope with these limits, the present study aims to develop a territorial-scale ERA on CECs previously identified by a "suspect screening" analytical approach (LC-QToF-MS) and quantified in the effluents of 10 WWTPs of a highly urbanized territory during three periods of the year. Among CECs, this work focused on pharmaceutical residue and pesticides. ERA was conducted following two complementary methods: (1) a single substance approach, based on the calculation for each CEC of risk quotients (RQs) by the ratio of Predicted Environmental Concentration (PEC) and Predicted No Effect Concentration (PNEC), and (2) mixture risk assessment ("cocktail effect") based on a concentration addition model (CA), summing individual RQs. Chemical results led to an ERA for 41 CEC (37 pharmaceuticals and 4 pesticides) detected in treated effluents. Single substance ERA identified 19 CECs implicated in at least one significant risk for streams, with significant risks for DEET, diclofenac, lidocaine, atenolol, terbutryn, atorvastatin, methocarbamol, and venlafaxine (RQs reaching 39.84, 62.10, 125.58, 179.11, 348.24, 509.27, 1509.71 and 3097.37, respectively). Mixture ERA allowed the identification of a risk (RQmix > 1) for 9 of the 10 WWTPs studied. It was also remarked that CECs leading individually to a negligible risk could imply a significant risk in a mixture. Finally, the territorial ERA showed a diversity of risk situations, with the highest concerns for 3 WWTPs: the 2 biggest of the territory discharging into a large French river, the Rhône, and for the smallest WWTP that releases into a small intermittent stream., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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158. ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation.
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Van Wyngene L, Vanderhaeghen T, Petta I, Timmermans S, Corbeels K, Van der Schueren B, Vandewalle J, Van Looveren K, Wallaeys C, Eggermont M, Dewaele S, Catrysse L, van Loo G, Beyaert R, Vangoitsenhoven R, Nakayama T, Tavernier J, De Bosscher K, and Libert C
- Abstract
The hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that regulates the body's response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), Zinc finger and BTB domain containing 32 (ZBTB32) is a transcription factor with poorly described functional relevance in physiology. This study shows that ZBTB32 is essential for the production of glucocorticoids (GCs) in response to starvation, since ZBTB32
-/- mice fail to increase their GC production in the absence of nutrients. In terms of mechanism, GR-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32-/- mice, implicating defective cholesterol import as the cause of the poor GC synthesis. These lower GC levels are further associated with aberrations in the metabolic adaptation to starvation, which could explain the progressive weight gain of ZBTB32-/- mice. In conclusion, ZBTB32 performs a crosstalk with the GR in the metabolic adaptation to starvation via regulation of adrenal GC production., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)- Published
- 2021
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159. Bidirectional Crosstalk Between Hypoxia Inducible Factors and Glucocorticoid Signalling in Health and Disease.
- Author
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Vanderhaeghen T, Beyaert R, and Libert C
- Subjects
- Animals, Glucocorticoids metabolism, Homeostasis, Humans, Hydrocortisone metabolism, Hypoxia-Inducible Factor 1 metabolism, Inflammation metabolism, Receptor Cross-Talk drug effects, Receptors, Glucocorticoid metabolism, Signal Transduction drug effects, Signal Transduction genetics, Glucocorticoids pharmacology, Hydrocortisone pharmacology, Hypoxia metabolism, Hypoxia-Inducible Factor 1 physiology, Receptor Cross-Talk physiology
- Abstract
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, in vitro and in vivo , and the therapeutic effects of GCs on HIF-mediated diseases., Competing Interests: The 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 Vanderhaeghen, Beyaert and Libert.)
- Published
- 2021
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160. Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.
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Virga F, Cappellesso F, Stijlemans B, Henze AT, Trotta R, Van Audenaerde J, Mirchandani AS, Sanchez-Garcia MA, Vandewalle J, Orso F, Riera-Domingo C, Griffa A, Ivan C, Smits E, Laoui D, Martelli F, Langouche L, Van den Berghe G, Feron O, Ghesquière B, Prenen H, Libert C, Walmsley SR, Corbet C, Van Ginderachter JA, Ivan M, Taverna D, and Mazzone M
- Subjects
- Animals, Inflammation genetics, Inflammation metabolism, Macrophages metabolism, Mice, Monocytes metabolism, MicroRNAs genetics, MicroRNAs metabolism, Sepsis genetics, Sepsis metabolism
- Abstract
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., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
- Published
- 2021
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161. Ratpost: a searchable database of protein-inactivating sequence variations in 40 sequenced rat-inbred strains.
- Author
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Timmermans S and Libert C
- Subjects
- Animals, Codon, Genome, Genomics methods, Open Reading Frames, Rats, Databases, Genetic, Proteins genetics, Proteins metabolism, Rats, Inbred Strains genetics, Rats, Inbred Strains metabolism
- Abstract
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.
- Published
- 2021
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162. Turning a pathogen protein into a therapeutic tool for sepsis.
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Vanderhaeghen T, Wallaeys C, and Libert C
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- Animals, Inflammation, Macrophages, Mice, Phagocytosis, Sepsis drug therapy
- Abstract
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., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2021
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163. Zinc inhibits lethal inflammatory shock by preventing microbe-induced interferon signature in intestinal epithelium.
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Souffriau J, Timmermans S, Vanderhaeghen T, Wallaeys C, Van Looveren K, Aelbrecht L, Dewaele S, Vandewalle J, Goossens E, Verbanck S, Boyen F, Eggermont M, De Commer L, De Rycke R, De Bruyne M, Tito R, Ballegeer M, Vandevyver S, Velho T, Moita LF, Hochepied T, De Bosscher K, Raes J, Van Immerseel F, Beyaert R, and Libert C
- Subjects
- Animals, Cell Death, Intestinal Mucosa, Mice, Paneth Cells, Interferons, Zinc
- Abstract
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., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2020
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164. Potential of glucocorticoids to treat intestinal inflammation during sepsis.
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Van Looveren K, Wallaeys C, and Libert C
- Subjects
- Animals, Humans, Anti-Inflammatory Agents therapeutic use, Glucocorticoids therapeutic use, Intestinal Diseases drug therapy, Sepsis drug therapy
- Abstract
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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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165. Glucocorticoids in Sepsis: To Be or Not to Be.
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Vandewalle J and Libert C
- Subjects
- Animals, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Receptors, Glucocorticoid metabolism, Sepsis metabolism, Glucocorticoids therapeutic use, Sepsis drug therapy
- Abstract
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., (Copyright © 2020 Vandewalle and Libert.)
- Published
- 2020
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166. Glucocorticoids limit lipopolysaccharide-induced lethal inflammation by a double control system.
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Van Looveren K, Timmermans S, Vanderhaeghen T, Wallaeys C, Ballegeer M, Souffriau J, Eggermont M, Vandewalle J, Van Wyngene L, De Bosscher K, and Libert C
- Subjects
- Animals, Cytokines, Glucocorticoids, Inflammation genetics, Mice, Tumor Necrosis Factor-alpha genetics, Endotoxemia chemically induced, Endotoxemia genetics, Lipopolysaccharides toxicity
- Abstract
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., (© 2020 The Authors.)
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- 2020
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167. Phytohormones: Multifunctional nutraceuticals against metabolic syndrome and comorbid diseases.
- Author
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Kim SW, Goossens A, Libert C, Van Immerseel F, Staal J, and Beyaert R
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- Diabetes Mellitus, Type 2 immunology, Diabetes Mellitus, Type 2 metabolism, Gastrointestinal Microbiome drug effects, Gastrointestinal Microbiome immunology, Humans, Inflammation, Metabolic Syndrome immunology, Metabolic Syndrome metabolism, Plant Growth Regulators biosynthesis, Diabetes Mellitus, Type 2 drug therapy, Dietary Supplements, Metabolic Syndrome drug therapy, Plant Growth Regulators pharmacology
- Abstract
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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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168. Taking the STING Out of Sepsis?
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Vandewalle J, Vanderhaeghen T, Beyaert R, and Libert C
- Subjects
- Animals, Disease Models, Animal, Macrophages, Mice, Membrane Proteins, Sepsis
- Abstract
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?, (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2020
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169. GILZ in sepsis: "Poor is the pupil who does not surpass his master".
- Author
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Vandewalle J and Libert C
- Subjects
- Animals, Glucocorticoids metabolism, Humans, Immunity, Innate, Immunomodulation, Transcription Factors genetics, Inflammation metabolism, Macrophages immunology, Monocytes immunology, Sepsis metabolism, Transcription Factors metabolism
- Abstract
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., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2020
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170. Hypoxia-inducible factors in metabolic reprogramming during sepsis.
- Author
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Vanderhaeghen T, Vandewalle J, and Libert C
- Subjects
- Animals, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Signal Transduction, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Sepsis metabolism
- Abstract
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., (© 2020 Federation of European Biochemical Societies.)
- Published
- 2020
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171. Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis.
- Author
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Van Wyngene L, Vanderhaeghen T, Timmermans S, Vandewalle J, Van Looveren K, Souffriau J, Wallaeys C, Eggermont M, Ernst S, Van Hamme E, Gonçalves A, Eelen G, Remmerie A, Scott CL, Rombouts C, Vanhaecke L, De Bus L, Decruyenaere J, Carmeliet P, and Libert C
- Subjects
- Animals, Humans, Lipids, Male, Metabolic Networks and Pathways, Mice, Mice, Inbred C57BL, Coinfection metabolism, Lipid Metabolism, Liver metabolism, PPAR alpha metabolism, Sepsis metabolism, Sepsis microbiology
- Abstract
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., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2020
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172. An extracellular microRNA can rescue lives in sepsis.
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Van Looveren K, Van Wyngene L, and Libert C
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- Aged, Anti-Bacterial Agents, Child, Child, Preschool, Humans, MicroRNAs, Sepsis
- Abstract
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 [
1 ]., (© 2019 The Authors.)- Published
- 2020
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173. Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization.
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Van Looveren K, Van Boxelaere M, Callaerts-Vegh Z, and Libert C
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- Animals, Behavior, Animal, Cognition, Cognitive Dysfunction genetics, Female, Glucocorticoids metabolism, Hippocampus metabolism, Male, Mice, Mutation, Protein Multimerization, Receptors, Glucocorticoid chemistry, Receptors, Glucocorticoid genetics, Cognitive Dysfunction metabolism, Receptors, Glucocorticoid metabolism
- Abstract
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., Competing Interests: The authors have declared that no competing interests exist.
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- 2019
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174. A Study of Cecal Ligation and Puncture-Induced Sepsis in Tissue-Specific Tumor Necrosis Factor Receptor 1-Deficient Mice.
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Vandewalle J, Steeland S, Van Ryckeghem S, Eggermont M, Van Wonterghem E, Vandenbroucke RE, and Libert C
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- Animals, Cecum microbiology, Disease Models, Animal, Endotoxemia etiology, Endotoxemia immunology, Female, Host Microbial Interactions immunology, Ligation, Lipopolysaccharides toxicity, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Organ Specificity, Punctures, Receptors, Tumor Necrosis Factor, Type I genetics, Receptors, Tumor Necrosis Factor, Type I immunology, Receptors, Tumor Necrosis Factor, Type II deficiency, Receptors, Tumor Necrosis Factor, Type II genetics, Receptors, Tumor Necrosis Factor, Type II immunology, Sepsis etiology, Sepsis microbiology, Receptors, Tumor Necrosis Factor, Type I deficiency, Sepsis immunology
- Abstract
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., (Copyright © 2019 Vandewalle, Steeland, Van Ryckeghem, Eggermont, Van Wonterghem, Vandenbroucke and Libert.)- Published
- 2019
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175. Mechanisms Underlying the Functional Cooperation Between PPARα and GRα to Attenuate Inflammatory Responses.
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Bougarne N, Mylka V, Ratman D, Beck IM, Thommis J, De Cauwer L, Tavernier J, Staels B, Libert C, and De Bosscher K
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- A549 Cells, Animals, Dexamethasone pharmacology, Glucocorticoids pharmacology, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Lipid Metabolism genetics, Lipopolysaccharides, Male, Mice, Inbred C57BL, NF-kappa B immunology, PPAR alpha agonists, Inflammation immunology, PPAR alpha immunology, Receptors, Glucocorticoid immunology
- Abstract
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. In vitro 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.
- Published
- 2019
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176. Overexpression of Gilz Protects Mice Against Lethal Septic Peritonitis.
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Ballegeer M, Vandewalle J, Eggermont M, Van Isterdael G, Dejager L, De Bus L, Decruyenaere J, Vandenbroucke RE, and Libert C
- Subjects
- Animals, Cecum injuries, Humans, Interleukin-6 blood, Leukocyte Common Antigens metabolism, Ligation adverse effects, Male, Mice, Mice, Inbred C57BL, Peritonitis blood, Peritonitis etiology, Phagocytosis genetics, Phagocytosis physiology, Punctures adverse effects, Sepsis etiology, Transcription Factors genetics, Peritonitis metabolism, Peritonitis prevention & control, Sepsis metabolism, Sepsis prevention & control, Transcription Factors metabolism
- Abstract
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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- 2019
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177. A General Introduction to Glucocorticoid Biology.
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Timmermans S, Souffriau J, and Libert C
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- Animals, Autoimmune Diseases drug therapy, Autoimmune Diseases immunology, Autoimmune Diseases pathology, Glucocorticoids therapeutic use, Humans, Metabolism, Inborn Errors immunology, Metabolism, Inborn Errors pathology, Metabolism, Inborn Errors therapy, Receptors, Glucocorticoid deficiency, Glucocorticoids immunology, Receptors, Glucocorticoid immunology
- Abstract
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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- 2019
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178. TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile.
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Dendoncker K, Timmermans S, Vandewalle J, Eggermont M, Lempiäinen J, Paakinaho V, Van Hamme E, Dewaele S, Vandevyver S, Ballegeer M, Souffriau J, Van Wyngene L, Van Looveren K, Vanderhaeghen T, Beyaert R, De Bosscher K, Palvimo JJ, Van Montagu M, and Libert C
- Subjects
- A549 Cells, Animals, Cell Nucleus drug effects, Cell Nucleus metabolism, Dexamethasone pharmacology, Dexamethasone therapeutic use, Down-Regulation drug effects, Down-Regulation immunology, E1A-Associated p300 Protein genetics, Female, Gene Knockdown Techniques, Glucocorticoids therapeutic use, HEK293 Cells, Humans, Inflammation immunology, Mice, NF-kappa B metabolism, Protein Interaction Mapping, Protein Interaction Maps drug effects, Protein Interaction Maps immunology, RNA, Small Interfering metabolism, RNA-Seq, Receptors, Glucocorticoid immunology, Up-Regulation drug effects, Up-Regulation immunology, Drug Resistance genetics, E1A-Associated p300 Protein metabolism, Glucocorticoids pharmacology, Inflammation drug therapy, Receptors, Glucocorticoid metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
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., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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179. Do people living with HIV experience greater age advancement than their HIV-negative counterparts?
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De Francesco D, Wit FW, Bürkle A, Oehlke S, Kootstra NA, Winston A, Franceschi C, Garagnani P, Pirazzini C, Libert C, Grune T, Weber D, Jansen EHJM, Sabin CA, and Reiss P
- Subjects
- Adult, Aged, Anti-Retroviral Agents therapeutic use, Cross-Sectional Studies, Female, HIV Infections drug therapy, Humans, Male, Middle Aged, Aging pathology, HIV Infections complications, HIV Infections pathology
- Abstract
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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- 2019
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180. Part II: Minimum Quality Threshold in Preclinical Sepsis Studies (MQTiPSS) for Types of Infections and Organ Dysfunction Endpoints.
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Libert C, Ayala A, Bauer M, Cavaillon JM, Deutschman C, Frostell C, Knapp S, Kozlov AV, Wang P, Osuchowski MF, and Remick DG
- Subjects
- Animals, Humans, Disease Models, Animal, Infections, Multiple Organ Failure, Shock, Septic
- Abstract
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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- 2019
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181. The Response to the Letter to the Editor Titled: "Is Triple Self-plagiarism "OK" If Only Made Transparent?" by Volker R Jacobs, MD, MBA.
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Osuchowski MF, Hellman J, Huber-Lang M, Libert C, Remick DG, Thiemermann C, and Zingarelli B
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- Animals, Consensus, Plagiarism, Sepsis
- Published
- 2019
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182. Should we target TNF receptors in the intestinal epithelium with glucocorticoids during systemic inflammation?
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Van Looveren K and Libert C
- Subjects
- Animals, Glucocorticoids pharmacology, Humans, Inflammation drug therapy, Inflammation physiopathology, Intestinal Mucosa metabolism, Molecular Targeted Therapy, Sepsis physiopathology, Systemic Inflammatory Response Syndrome physiopathology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Receptors, Tumor Necrosis Factor, Type I metabolism, Sepsis drug therapy, Systemic Inflammatory Response Syndrome drug therapy
- Abstract
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.
- Published
- 2018
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183. Easy Access to and Applications of the Sequences of All Protein-Coding Genes of All Sequenced Mouse Strains.
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Timmermans S and Libert C
- Subjects
- Amino Acid Sequence, Animals, Computational Biology, Mice, Mice, Inbred C57BL genetics, Molecular Sequence Annotation, Sequence Analysis, DNA, Databases, Genetic, Genome genetics, Mice, Inbred Strains genetics, Proteins genetics
- Abstract
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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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184. Inhibition of MALT1 Decreases Neuroinflammation and Pathogenicity of Virulent Rabies Virus in Mice.
- Author
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Kip E, Staal J, Tima HG, Verstrepen L, Romano M, Lemeire K, Suin V, Hamouda A, Baens M, Libert C, Kalai M, Van Gucht S, and Beyaert R
- Subjects
- Animals, Brain metabolism, Brain virology, Cells, Cultured, Inflammation immunology, Inflammation metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein antagonists & inhibitors, Rabies immunology, Rabies metabolism, T-Lymphocytes pathology, T-Lymphocytes virology, Brain immunology, Inflammation prevention & control, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein physiology, Rabies prevention & control, Rabies virus immunology, T-Lymphocytes immunology
- Abstract
Rabies virus is a neurovirulent RNA virus, which causes about 59,000 human deaths each year. Treatment for rabies does not exist due to incomplete understanding of the pathogenesis. MALT1 mediates activation of several immune cell types and is involved in the proliferation and survival of cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, leading to the expression of immunoregulatory genes. Here, we examined the impact of genetic or pharmacological MALT1 inhibition in mice on disease development after infection with the virulent rabies virus strain CVS-11. Morbidity and mortality were significantly delayed in Malt1
-/- compared to Malt1+/+ mice, and this effect was associated with lower viral load, proinflammatory gene expression, and infiltration and activation of immune cells in the brain. Specific deletion of Malt1 in T cells also delayed disease development, while deletion in myeloid cells, neuronal cells, or NK cells had no effect. Disease development was also delayed in mice treated with the MALT1 protease inhibitor mepazine and in knock-in mice expressing a catalytically inactive MALT1 mutant protein, showing an important role of MALT1 proteolytic activity. The described protective effect of MALT1 inhibition against infection with a virulent rabies virus is the precise opposite of the sensitizing effect of MALT1 inhibition that we previously observed in the case of infection with an attenuated rabies virus strain. Together, these data demonstrate that the role of immunoregulatory responses in rabies pathogenicity is dependent on virus virulence and reveal the potential of MALT1 inhibition for therapeutic intervention. IMPORTANCE Rabies virus is a neurotropic RNA virus that causes encephalitis and still poses an enormous challenge to animal and public health. Efforts to establish reliable therapeutic strategies have been unsuccessful and are hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protease that mediates the activation of several innate and adaptive immune cells in response to multiple receptors, and therapeutic MALT1 targeting is believed to be a valid approach for autoimmunity and MALT1-addicted cancers. Here, we study the impact of MALT1 deficiency on brain inflammation and disease development in response to infection of mice with the highly virulent CVS-11 rabies virus. We demonstrate that pharmacological or genetic MALT1 inhibition decreases neuroinflammation and extends the survival of CVS-11-infected mice, providing new insights in the biology of MALT1 and rabies virus infection., (Copyright © 2018 American Society for Microbiology.)- Published
- 2018
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185. Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): An International Expert Consensus Initiative for Improvement of Animal Modeling in Sepsis.
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Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon JM, Chaudry IH, Coopersmith CM, Deutschman CS, Drechsler S, Efron P, Frostell C, Fritsch G, Gozdzik W, Hellman J, Huber-Lang M, Inoue S, Knapp S, Kozlov AV, Libert C, Marshall JC, Moldawer LL, Radermacher P, Redl H, Remick DG, Singer M, Thiemermann C, Wang P, Wiersinga WJ, Xiao X, and Zingarelli B
- Subjects
- Animals, Biomedical Research standards, Consensus, Disease Models, Animal, Sepsis
- Abstract
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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- 2018
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186. Correction to: Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis.
- Author
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Osuchowski MF, Ayala A, Bahrami S, Bauer M, Boros M, Cavaillon JM, Chaudry IH, Coopersmith CM, Deutschman C, Drechsler S, Efron P, Frostell C, Fritsch G, Gozdzik W, Hellman J, Huber-Lang M, Inoue S, Knapp S, Kozlov AV, Libert C, Marshall JC, Moldawer LL, Radermacher P, Redl H, Remick DG, Singer M, Thiemermann C, Wang P, Wiersinga WJ, Xiao X, and Zingarelli B
- Abstract
The original version of this article unfortunately contained mistakes.
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- 2018
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187. IFN-γ stimulates CpG-induced IL-10 production in B cells via p38 and JNK signalling pathways.
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Imbrechts M, De Samblancx K, Fierens K, Brisse E, Vandenhaute J, Mitera T, Libert C, Smets I, Goris A, Wouters C, and Matthys P
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, Cell Proliferation genetics, Cells, Cultured, Dual Specificity Phosphatase 1 biosynthesis, Humans, Interferon-gamma genetics, Lymphocyte Activation genetics, MAP Kinase Signaling System genetics, Macrophages immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Receptor, Interferon alpha-beta genetics, Signal Transduction immunology, B-Lymphocytes immunology, CpG Islands genetics, Interferon-gamma metabolism, Interleukin-10 biosynthesis, JNK Mitogen-Activated Protein Kinases metabolism, Toll-Like Receptor 9 metabolism, p38 Mitogen-Activated Protein Kinases metabolism
- Abstract
The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-γ, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes and macrophages, but also has some regulatory functions. In the present study, we explored the role of IFN-γ on Toll-like receptor (TLR)-induced IL-10 production in murine peritoneal and spleen cells and in human peripheral blood mononuclear cells. IFN-γ inhibited IL-10 production induced by TLR2, TLR3, TLR4 and TLR7/8 agonists, but stimulated IL-10 production when cells were triggered with CpG oligodeoxynucleotides, a specific TLR9 agonist. The stimulatory effect of IFN-γ on TLR9-induced IL-10 was restricted to B cells. In line with the increased IL-10, B cells stimulated with CpG and IFN-γ profoundly inhibited CD4 T cell proliferation. Further research into the mechanisms involved, revealed that the mitogen-activated protein kinases p38 and JNK are essential players in this stimulatory effect, and that the phosphatase MKP1 - an inhibitor of p38 and JNK activity - is downregulated after combined stimulation with IFN-γ and CpG. Our data may represent a novel immunoregulatory role of IFN-γ in B cells after triggering of TLR9, by stimulating IL-10 production., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2018
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188. A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation.
- Author
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Souffriau J, Eggermont M, Van Ryckeghem S, Van Looveren K, Van Wyngene L, Van Hamme E, Vuylsteke M, Beyaert R, De Bosscher K, and Libert C
- Subjects
- A549 Cells, Animals, Anti-Inflammatory Agents chemistry, Dexamethasone pharmacology, Disease Models, Animal, Female, Gene Expression Regulation drug effects, Genes, Reporter, Humans, Inflammation drug therapy, Inflammation etiology, Inflammation metabolism, Mice, Protein Binding, Pyridines pharmacology, Receptors, Glucocorticoid agonists, Response Elements, Transcriptional Activation, Anti-Inflammatory Agents pharmacology, Drug Discovery methods, Drug Evaluation, Preclinical methods, Protein Multimerization, Receptors, Glucocorticoid chemistry
- Abstract
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.
- Published
- 2018
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189. Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice.
- Author
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Ballegeer M, Van Looveren K, Timmermans S, Eggermont M, Vandevyver S, Thery F, Dendoncker K, Souffriau J, Vandewalle J, Van Wyngene L, De Rycke R, Takahashi N, Vandenabeele P, Tuckermann J, Reichardt HM, Impens F, Beyaert R, De Bosscher K, Vandenbroucke RE, and Libert C
- Subjects
- Animals, Humans, Inflammation drug therapy, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases pathology, Mice, Mice, Knockout, Protein Multimerization genetics, Receptors, Glucocorticoid genetics, Response Elements, STAT1 Transcription Factor genetics, Tumor Necrosis Factor-alpha genetics, Dexamethasone pharmacology, Inflammatory Bowel Diseases metabolism, Protein Multimerization drug effects, Receptors, Glucocorticoid metabolism, STAT1 Transcription Factor metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
TNF is an important mediator in numerous inflammatory diseases, e.g., in inflammatory bowel diseases (IBDs). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRWT/WT mice, these GRdim/dim mice displayed a substantial increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong IFN-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes, resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay among gut microbiota, IFNs, necroptosis, and GR in both the basal response to acute inflammatory challenges and pharmacological intervention by GCs.
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- 2018
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190. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?
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Van Wyngene L, Vandewalle J, and Libert C
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- Animals, Blood Glucose metabolism, Epigenesis, Genetic, Glycolysis, Humans, Hyperglycemia metabolism, Hypoglycemia metabolism, Hypoxia metabolism, Inflammation metabolism, Ketone Bodies biosynthesis, Lipolysis, Metabolic Networks and Pathways, Mice, Mitochondria metabolism, Peroxisome Proliferator-Activated Receptors metabolism, Rats, Sepsis blood, Sepsis diagnosis, Sepsis genetics, Sepsis metabolism
- Abstract
Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2018
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191. Using the inbred mouse strain SPRET/EiJ to provide novel insights in inflammation and infection research.
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Timmermans S, Souffriau J, Vandewalle J, Van Wyngene L, Van Looveren K, Vanderhaeghen T, and Libert C
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- Animals, Disease Resistance genetics, Disease Resistance immunology, Genetic Background, Genetic Variation, Genome, Genomics methods, Lipopolysaccharides immunology, Mice, Species Specificity, Disease Susceptibility, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Infections etiology, Inflammation etiology, Mice, Inbred Strains
- Abstract
Inbred mouse strains derived from the species Mus spretus have been very informative in the study of certain gene polymorphisms in inflammation and infection. Based on our interest in sepsis, we used SPRET/EiJ mice and mapped several critical loci that are linked to sensitivity to cytokine-induced inflammation and endotoxemia. These studies were based on prominent phenotypes that have never been observed in strains derived from Mus musculus and we mapped them at a resolution that enables us to draw conclusions on the mechanisms. Now that the genome of SPRET/EiJ has been sequenced, and other tools have become available, it is time to revisit this strain and emphasize its advantages and disadvantages as a research tool and a discovery platform.
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- 2018
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192. Overview of inactivating mutations in the protein-coding genome of the mouse reference strain C57BL/6J.
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Timmermans S and Libert C
- Subjects
- Animals, Bone Density, Genetic Variation, Mice, Mice, Inbred C57BL genetics, Phenotype, Receptors, Chemokine, Sequence Alignment, Toll-Like Receptors, Toxoplasma, Genome genetics, Mice, Inbred Strains genetics, Mutation, Proteins genetics
- Abstract
Mice are extremely important as the premier model organism in human biomedical and mammalian genetic research. The genomes of several tens of mouse inbred strains have been sequenced. They have been compared to the genome of C57BL/6J, considered by convention as the reference genome. Based on a comparison of this reference genome with 36 other sequenced mouse strains, we generated an overview of all protein-coding genes that are deviant in this reference genome, compared with consensus protein-coding mouse gene sequences. We provide PROVEAN scores, reflecting the likelihood that these C57BL/6J proteins have lost function. We thus identified numerous abnormal proteins, and biological pathways, specifically present in C57BL/6J, suggesting the important caveats of this reference mouse strain, and linking candidate genes to some of the best-known phenotypes of this strain.
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- 2018
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193. The E3 ubiquitin ligases HOIP and cIAP1 are recruited to the TNFR2 signaling complex and mediate TNFR2-induced canonical NF-κB signaling.
- Author
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Borghi A, Haegman M, Fischer R, Carpentier I, Bertrand MJM, Libert C, Afonina IS, and Beyaert R
- Subjects
- Animals, HeLa Cells, Humans, Mice, Ubiquitination physiology, Inhibitor of Apoptosis Proteins metabolism, NF-kappa B metabolism, Receptors, Tumor Necrosis Factor, Type II metabolism, Signal Transduction physiology, Ubiquitin-Protein Ligases metabolism
- Abstract
Tumor Necrosis Factor (TNF) is a proinflammatory cytokine that elicits its action by binding to two cell surface TNF receptors (TNFR), TNFR1 and TNFR2, which are expressed by many different cell types. Stimulation of TNFR1 activates canonical NF-κB signaling, leading to the NF-κB dependent expression of a large number of genes. Canonical NF-κB signaling requires the assembly of a TNFR1 signaling complex at the cell membrane, whose formation is regulated by different protein ubiquitination events. In this context, recruitment of the Linear Ubiquitin Chain Assembly Complex (LUBAC) to TNFR1 plays an important role by mediating M1-linked polyubiquitination of specific NF-κB signaling proteins. In contrast to TNFR1, much less is known about the role of ubiquitination in TNFR2 signaling. Here we demonstrate that specific TNFR2 stimulation rapidly triggers M1- and K63-linked polyubiquitination at the TNFR2 signaling complex. In agreement, TNFR2 stimulation induces the recruitment of HOIP, a LUBAC component and the only known E3 ubiquitin ligase for M1-polyubiquitination, to the TNFR2 signaling complex. Also cIAP1, a E3 ubiquitin ligase able to modify proteins with K63-polyubiquitin chains, was recruited to the TNFR2 signaling complex. Treatment of cells with a cIAP antagonist inhibited the recruitment of HOIP and prevented HOIP-mediated M1-ubiquitination of the TNFR2 signaling complex, indicating that HOIP recruitment to the TNFR2 relies on cIAPs. Finally, we show that both HOIP and cIAP1 are required for TNFR2-induced canonical NF-κB activation. Together, our findings demonstrate an important role for M1- and K63-linked polyubiquitination in TNFR2 signaling., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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194. Alterations of the serum N-glycan profile in female patients with Major Depressive Disorder.
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Boeck C, Pfister S, Bürkle A, Vanhooren V, Libert C, Salinas-Manrique J, Dietrich DE, Kolassa IT, and Karabatsiakis A
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- Aged, Biomarkers blood, C-Reactive Protein analysis, Case-Control Studies, Depressive Disorder, Major complications, Female, Humans, Inflammation complications, Interleukin-6 blood, Middle Aged, Tumor Necrosis Factor-alpha blood, Depressive Disorder, Major blood, Inflammation blood, Polysaccharides blood
- Abstract
Background: Glycans are short chains of saccharides linked to glycoproteins that are known to be involved in a wide range of inflammatory processes. As depression has been consistently associated with chronic low-grade inflammation, we asked whether patients with Major Depressive Disorder show alterations in the N-glycosylation pattern of serum proteins that might be linked to associated changes in inflammatory processes., Methods: In a study cohort of 21 female patients with an acute depressive episode and 21 non-depressed female control subjects aged between 50 and 69 years, we analyzed the serum N-glycan profile by DNA Sequencer Adapted-Fluorophore Assisted Carbohydrate Electrophoresis (DSA-FACE) and assessed the serum levels of interleukin (IL)- 6, tumor necrosis factor (TNF)-α and C-reactive protein (CRP) by chemiluminescence immunoassays and nephelometry., Results: Compared to controls, MDD patients showed significant differences in the serum levels of several N-glycan structures. Alterations in the serum N-glycan profile were associated with depressive symptom severity and exploratory analyses revealed that they were most pronounced in MDD patients with a history of childhood sexual abuse. Furthermore, MDD patients showed higher levels of IL-6 and a trend for higher CRP levels, which were also associated with similar alterations in the serum N-glycan profile as those characteristic for MDD patients., Limitations: The relatively small sample size and the presence of potential confounders (e.g., BMI, smoking, medication)., Conclusion: The results offer the first evidence that specific differences in the N-glycosylation pattern of serum proteins constitute a so far unrecognized level of biological alterations that might be involved in the immune changes associated with MDD., (Copyright © 2018 Elsevier B.V. All rights reserved.)
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- 2018
- Full Text
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195. A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation.
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Voet S, Mc Guire C, Hagemeyer N, Martens A, Schroeder A, Wieghofer P, Daems C, Staszewski O, Vande Walle L, Jordao MJC, Sze M, Vikkula HK, Demeestere D, Van Imschoot G, Scott CL, Hoste E, Gonçalves A, Guilliams M, Lippens S, Libert C, Vandenbroucke RE, Kim KW, Jung S, Callaerts-Vegh Z, Callaerts P, de Wit J, Lamkanfi M, Prinz M, and van Loo G
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Brain immunology, Brain pathology, Disease Models, Animal, Female, Humans, Interleukin-1beta metabolism, Lipopolysaccharides immunology, Male, Mice, Microglia pathology, Middle Aged, Multiple Sclerosis cerebrospinal fluid, Multiple Sclerosis pathology, NLR Family, Pyrin Domain-Containing 3 Protein immunology, Signal Transduction immunology, Tumor Necrosis Factor alpha-Induced Protein 3 genetics, Tumor Necrosis Factor alpha-Induced Protein 3 immunology, Inflammasomes immunology, Microglia immunology, Multiple Sclerosis immunology, Tumor Necrosis Factor alpha-Induced Protein 3 metabolism
- Abstract
Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency. Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1β expression in brain and cerebrospinal fluid from MS patients. Collectively, these data reveal a critical role for A20 in the control of microglia activation and neuroinflammation.
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- 2018
- Full Text
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196. Learning lessons in sepsis from the children.
- Author
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Timmermans S and Libert C
- Subjects
- Child, Humans, Learning, Sepsis
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- 2018
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- View/download PDF
197. A New Venue of TNF Targeting.
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Steeland S, Libert C, and Vandenbroucke RE
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- Animals, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal therapeutic use, Disease Susceptibility, Humans, Immunomodulation, Inflammation Mediators metabolism, Protein Binding, Receptors, Tumor Necrosis Factor metabolism, Signal Transduction, Tumor Necrosis Factors genetics, Tumor Necrosis Factors metabolism, Tumor Necrosis Factors pharmacology, Receptors, Tumor Necrosis Factor antagonists & inhibitors, Tumor Necrosis Factor Inhibitors
- Abstract
The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-tumor necrosis factor (TNF) drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn's disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class, whereas others are linked with their mechanism of action, being pan-TNF inhibition. The effects of TNF can diverge at the level of TNF format or receptor, and we discuss the consequences of this in sepsis, autoimmunity and neurodegeneration. Recently, researchers tried to design drugs with reduced side effects. These include molecules with more specificity targeting one specific TNF format or receptor, or that neutralize TNF in specific cells. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the benefits of selective approaches in different diseases., Competing Interests: The authors declare no conflict of interest.
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- 2018
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198. Genetic mapping of species differences via in vitro crosses in mouse embryonic stem cells.
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Lazzarano S, Kučka M, Castro JPL, Naumann R, Medina P, Fletcher MNC, Wombacher R, Gribnau J, Hochepied T, Van Montagu M, Libert C, and Chan YF
- Subjects
- Animals, Antimetabolites, Antineoplastic pharmacology, Biological Evolution, Cells, Cultured, Chromosome Mapping, Drug Resistance genetics, Female, Hybridization, Genetic, In Vitro Techniques, Mice, Mice, Inbred C57BL, Mouse Embryonic Stem Cells drug effects, Mouse Embryonic Stem Cells metabolism, Phenotype, Pregnancy, RecQ Helicases antagonists & inhibitors, Species Specificity, Thioguanine pharmacology, Crosses, Genetic, Mouse Embryonic Stem Cells cytology, Quantitative Trait Loci
- Abstract
Discovering the genetic changes underlying species differences is a central goal in evolutionary genetics. However, hybrid crosses between species in mammals often suffer from hybrid sterility, greatly complicating genetic mapping of trait variation across species. Here, we describe a simple, robust, and transgene-free technique to generate "in vitro crosses" in hybrid mouse embryonic stem (ES) cells by inducing random mitotic cross-overs with the drug ML216, which inhibits the DNA helicase Bloom syndrome (BLM). Starting with an interspecific F1 hybrid ES cell line between the Mus musculus laboratory mouse and Mus spretus (∼1.5 million years of divergence), we mapped the genetic basis of drug resistance to the antimetabolite tioguanine to a single region containing hypoxanthine-guanine phosphoribosyltransferase ( Hprt ) in as few as 21 d through "flow mapping" by coupling in vitro crosses with fluorescence-activated cell sorting (FACS). We also show how our platform can enable direct study of developmental variation by rederiving embryos with contribution from the recombinant ES cell lines. We demonstrate how in vitro crosses can overcome major bottlenecks in mouse complex trait genetics and address fundamental questions in evolutionary biology that are otherwise intractable through traditional breeding due to high cost, small litter sizes, and/or hybrid sterility. In doing so, we describe an experimental platform toward studying evolutionary systems biology in mouse and potentially in human and other mammals, including cross-species hybrids., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)
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- 2018
- Full Text
- View/download PDF
199. Counteracting the effects of TNF receptor-1 has therapeutic potential in Alzheimer's disease.
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Steeland S, Gorlé N, Vandendriessche C, Balusu S, Brkic M, Van Cauwenberghe C, Van Imschoot G, Van Wonterghem E, De Rycke R, Kremer A, Lippens S, Stopa E, Johanson CE, Libert C, and Vandenbroucke RE
- Subjects
- Alzheimer Disease genetics, Animals, Cytokines metabolism, Enzyme-Linked Immunosorbent Assay, Female, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microscopy, Electron, Scanning, Microscopy, Electron, Transmission, Real-Time Polymerase Chain Reaction, Receptors, Tumor Necrosis Factor, Type I genetics, Alzheimer Disease metabolism, Choroid Plexus cytology, Choroid Plexus metabolism, Receptors, Tumor Necrosis Factor, Type I metabolism
- Abstract
Alzheimer's disease (AD) is the most common form of dementia, and neuroinflammation is an important hallmark of the pathogenesis. Tumor necrosis factor (TNF) might be detrimental in AD, though the results coming from clinical trials on anti-TNF inhibitors are inconclusive. TNFR1, one of the TNF signaling receptors, contributes to the pathogenesis of AD by mediating neuronal cell death. The blood-cerebrospinal fluid (CSF) barrier consists of a monolayer of choroid plexus epithelial (CPE) cells, and AD is associated with changes in CPE cell morphology. Here, we report that TNF is the main inflammatory upstream mediator in choroid plexus tissue in AD patients. This was confirmed in two murine AD models: transgenic APP/PS1 mice and intracerebroventricular (icv) AβO injection. TNFR1 contributes to the morphological damage of CPE cells in AD, and TNFR1 abrogation reduces brain inflammation and prevents blood-CSF barrier impairment. In APP/PS1 transgenic mice, TNFR1 deficiency ameliorated amyloidosis. Ultimately, genetic and pharmacological blockage of TNFR1 rescued from the induced cognitive impairments. Our data indicate that TNFR1 is a promising therapeutic target for AD treatment., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2018
- Full Text
- View/download PDF
200. The 'COmorBidity in Relation to AIDS' (COBRA) cohort: Design, methods and participant characteristics.
- Author
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De Francesco D, Wit FW, Cole JH, Kootstra NA, Winston A, Sabin CA, Underwood J, van Zoest RA, Schouten J, Kooij KW, Prins M, Guaraldi G, Caan MWA, Burger D, Franceschi C, Libert C, Bürkle A, and Reiss P
- Subjects
- Acquired Immunodeficiency Syndrome complications, Acquired Immunodeficiency Syndrome drug therapy, Anti-HIV Agents therapeutic use, Comorbidity, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, Netherlands, Socioeconomic Factors, United Kingdom, Acquired Immunodeficiency Syndrome epidemiology, Noncommunicable Diseases epidemiology
- Abstract
Background: Persons living with HIV on combination antiretroviral therapy (cART) may be at increased risk of the development of age-associated non-communicable comorbidities (AANCC) at relatively young age. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated aging., Objective: The COmorBidity in Relation to AIDS (COBRA) cohort study was designed to investigate the potential causal link between HIV and AANCC, amongst others, in a cohort of middle-aged individuals with HIV with sustained viral suppression on cART and otherwise comparable HIV-negative controls., Methods: Longitudinal cohort study of HIV-positive subjects ≥45 years of age, with sustained HIV suppression on cART recruited from two large European HIV treatment centres and similarly-aged HIV-negative controls recruited from sexual health centres and targeted community groups. Both HIV-positive and HIV-negative subjects were assessed at study entry and again at follow-up after 2 years., Results: Of the 134 HIV-positive individuals with a median (IQR) age of 56 (51, 62) years recruited, 93% were male, 88% of white ethnicity and 86% were men who have sex with men (MSM). Similarly, the 79 HIV-negative subjects had a median (IQR) age of 57 (52, 64) and 92% were male, 97% of white ethnicity and 80% were MSM., Conclusions: The results from the COBRA study will be a significant resource to understand the link between HIV and AANCC and the pathogenic mechanisms underlying this link. COBRA will inform future development of novel prognostic tools for earlier diagnosis of AANCC and of novel interventions which, as an adjunct to cART, may prevent AANCC.
- Published
- 2018
- Full Text
- View/download PDF
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