Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    How the COVID-19 pandemic highlights the necessity of animal research
    Genzel, Lisa ; Adan, Roger ; Berns, Anton ; Beucken, Jeroen van den; Blokland, Arjan ; Boddeke, Erik H.W.G.M. ; Bogers, Willy M. ; Bontrop, Ronald ; Bulthuis, R. ; Bousema, Teun ; Clevers, Hans ; Coenen, Tineke C.J.J. ; Dam, Anne Marie van; Deen, Peter M.T. ; Dijk, K.W. van; Eggen, Bart J.L. ; Elgersma, Ype ; Erdogan, Izel ; Englitz, Bernard ; Fentener van Vlissingen, J.M. ; Fleur, Susanne la; Fouchier, Ron ; Fitzsimons, Carlos P. ; Frieling, Wilbert ; Haagmans, Bart ; Heesters, Balthasar A. ; Henckens, Marloes ; Herfst, Sander ; Hol, Elly ; Hove, Daniel van den; Jonge, Marien I. de; Jonkers, Jos ; Joosten, Leo A.B. ; Kalsbeek, Andries ; Kamermans, Maarten ; Kampinga, Harm H. ; Kas, Martien J. ; Keijer, J. ; Kersten, Sander ; Kiliaan, Amanda J. ; Kooij, Taco W.A. ; Kooijman, Sander ; Koopman, Werner J.H. ; Korosi, Aniko ; Krugers, Harm J. ; Kuiken, Thijs ; Kushner, Steven A. ; Langermans, Jan A.M. ; Lesscher, Heidi ; Lucassen, Paul J. ; Lutgens, Esther ; Netea, Mihai G. ; Noldus, Lucas P.J.J. ; Meer, Jos W.M. van der; Meye, Frank J. ; Mul, Joram D. ; Oers, Kees van; Olivier, Jocelien D.A. ; Pasterkamp, R.J. ; Philippens, Ingrid H.C.H.M. ; Prickaerts, Jos ; Pullox, Bart J.A. ; Rensen, Patrick C.N. ; Rheenen, Jacco van; Rij, Ronald P. van; Ritsma, Laila ; Rockx, Barry H.G. ; Roozendaal, Benno ; Schothorst, Evert M. van; Stittelaar, K. ; Stockhofe, Norbert ; Swaab, Dick F. ; Swart, Rik L. de; Vanderschuren, Louk J.M.J. ; Vries, Taco de; Vrij, Femke de; Wezel, Richard van; Wierenga, Corette J. ; Wiesmann, Maximilian ; Willuhn, Ingo ; Zeeuw, Chris I. de; Homberg, Judith R. - \ 2020
    Current Biology 30 (2020)18. - ISSN 0960-9822 - p. R1014 - R1018.
    Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health. In this Essay, Genzel et al. make the case for animal research in light of the COVID-19 pandemic.
    Correction to: Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
    Keating, Samuel T. ; Groh, Laszlo ; Thiem, Kathrin ; Bekkering, Siroon ; Li, Yang ; Matzaraki, Vasiliki ; Heijden, Charlotte D.C.C. van der; Puffelen, Jelmer H. van; Lachmandas, Ekta ; Jansen, Trees ; Oosting, Marije ; Bree, L.C.J. de; Koeken, Valerie A.C.M. ; Moorlag, Simone J.C.F.M. ; Mourits, Vera P. ; Diepen, Janna van; Stienstra, Rinke ; Novakovic, Boris ; Stunnenberg, Hendrik G. ; Crevel, Reinout van; Joosten, Leo A.B. ; Netea, Mihai G. ; Riksen, Niels P. - \ 2020
    Journal of Molecular Medicine 98 (2020). - ISSN 0946-2716

    The correct name of the 17th Author is presented in this paper. In the paragraph “Metabolic analysis” of the Method section “an XFp Analyzer” should be changed to “an XFe96 Analyzer”.

    Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
    Keating, Samuel T. ; Groh, Laszlo ; Thiem, Kathrin ; Bekkering, Siroon ; Li, Yang ; Matzaraki, Vasiliki ; Heijden, Charlotte D.C.C. van der; Puffelen, Jelmer H. van; Lachmandas, Ekta ; Jansen, Trees ; Oosting, Marije ; Bree, L.C.J. de; Koeken, Valerie A.C.M. ; Moorlag, Simone J.C.F.M. ; Mourits, Vera P. ; Diepen, Janna van; Stienstra, Rinke ; Novakovic, Boris ; Stunnenberg, Hendrik G. ; Crevel, Reinout van; Joosten, Leo A.B. ; Netea, Mihai G. ; Riksen, Niels P. - \ 2020
    Journal of Molecular Medicine 98 (2020). - ISSN 0946-2716 - p. 819 - 831.
    Atherosclerosis - Cardiovascular disease - Diabetes complications - Glycolysis - Immunometabolism - Inflammation - Trained immunity

    Abstract: Stimulation of monocytes with microbial and non-microbial products, including oxidized low-density lipoprotein (oxLDL), induces a protracted pro-inflammatory, atherogenic phenotype sustained by metabolic and epigenetic reprogramming via a process called trained immunity. We investigated the intracellular metabolic mechanisms driving oxLDL-induced trained immunity in human primary monocytes and observed concomitant upregulation of glycolytic activity and oxygen consumption. In two separate cohorts of healthy volunteers, we assessed the impact of genetic variation in glycolytic genes on the training capacity of monocytes and found that variants mapped to glycolytic enzymes PFKFB3 and PFKP influenced trained immunity by oxLDL. Subsequent functional validation with inhibitors of glycolytic metabolism revealed dose-dependent inhibition of trained immunity in vitro. Furthermore, in vivo administration of the glucose metabolism modulator metformin abrogated the ability for human monocytes to mount a trained response to oxLDL. These findings underscore the importance of cellular metabolism for oxLDL-induced trained immunity and highlight potential immunomodulatory strategies for clinical management of atherosclerosis. Key messages: Brief stimulation of monocytes to oxLDL induces a prolonged inflammatory phenotype.This is due to upregulation of glycolytic metabolism.Genetic variation in glycolytic genes modulates oxLDL-induced trained immunity.Pharmacological inhibition of glycolysis prevents trained immunity.

    Heritability estimates for 361 blood metabolites across 40 genome-wide association studies
    Hagenbeek, Fiona A. ; Pool, René ; Dongen, Jenny van; Draisma, H.M. ; Jan Hottenga, Jouke ; Willemsen, Gonneke ; Abdellaoui, Abdel ; Fedko, Iryna O. ; Braber, Anouk den; Visser, Pieter Jelle ; Geus, Eco J.C.N. de; Willems van Dijk, Ko ; Verhoeven, Aswin ; Suchiman, H.E. ; Beekman, Marian ; Slagboom, P.E. ; Duijn, Cornelia M. van; Barkey Wolf, J.J.H. ; Cats, D. ; Amin, N. ; Beulens, J.W. ; Bom, J.A. van der; Bomer, N. ; Demirkan, A. ; Hilten, J.A. van; Meessen, J.M.T.A. ; Moed, M.H. ; Fu, J. ; Onderwater, G.L.J. ; Rutters, F. ; So-Osman, C. ; Flier, W.M. van der; Heijden, A.A.W.A. van der; Spek, A. van der; Asselbergs, F.W. ; Boersma, E. ; Elders, P.M. ; Geleijnse, J.M. ; Ikram, M.A. ; Kloppenburg, M. ; Meulenbelt, I. ; Mooijaart, S.P. ; Nelissen, R.G.H.H. ; Netea, M.G. ; Penninx, B.W.J.H. ; Stehouwer, C.D.A. ; Teunissen, C.E. ; Terwindt, G.M. ; Jukema, J.W. ; Reinders, M.J.T. - \ 2020
    Nature Communications 11 (2020)1. - ISSN 2041-1723

    The original version of the Supplementary Information associated with this Article included an incorrect Supplementary Data 1 file, in which additional delimiters were included in the first column for a number of rows, resulting in column shifts for some of these rows. The HTML has been updated to include a corrected version of Supplementary Data 1; the original incorrect version of Supplementary Data 1 can be found as Supplementary Information associated with this Correction. In addition, the original version of this Article contained an error in the author affiliations. An affiliation of Abdel Abdellaoui with Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.

    Involvement of lactate and pyruvate in the anti-inflammatory effects exerted by voluntary activation of the sympathetic nervous system
    Zwaag, Jelle ; Horst, Robter ; Blaženovic, Ivana ; Stoessel, Daniel ; Ratter, Jacqueline ; Worseck, Josephine M. ; Schauer, Nicolas ; Stienstra, Rinke ; Netea, Mihai G. ; Jahn, Dieter ; Pickkers, Peter ; Kox, Matthijs - \ 2020
    Metabolites 10 (2020)4. - ISSN 2218-1989

    We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether this training program affects the plasma metabolome and if these changes are linked to the immunomodulatory effects observed. A total of 224 metabolites were identified in plasma obtained from 24 healthy male volunteers at six timepoints, of which 98 were significantly altered following LPS administration. Effects of the training program were most prominent shortly after initiation of the acquired breathing exercises but prior to LPS administration, and point towards increased activation of the Cori cycle. Elevated concentrations of lactate and pyruvate in trained individuals correlated with enhanced levels of anti-inflammatory interleukin (IL)-10. In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1β and IL-6 by LPS-stimulated leukocytes. Our results demonstrate that practicing the breathing exercises acquired during the training program results in increased activity of the Cori cycle. Furthermore, this work uncovers an important role of lactate and pyruvate in the anti-inflammatory phenotype observed in trained subjects.

    Trained Immunity: Linking Obesity and Cardiovascular Disease across the Life-Course?
    Bekkering, Siroon ; Saner, Christoph ; Riksen, Niels P. ; Netea, Mihai G. ; Sabin, Matthew A. ; Saffery, Richard ; Stienstra, Rinke ; Burgner, David P. - \ 2020
    Trends in Endocrinology & Metabolism 31 (2020)5. - ISSN 1043-2760 - p. 378 - 389.
    atherosclerosis - cardiovascular disease - inflammation - obesity - trained immunity

    Obesity, a chronic inflammatory disease, is the most prevalent modifiable risk factor for cardiovascular disease. The mechanisms underlying inflammation in obesity are incompletely understood. Recent developments have challenged the dogma of immunological memory occurring exclusively in the adaptive immune system and show that the innate immune system has potential to be reprogrammed. This innate immune memory (trained immunity) is characterized by epigenetic and metabolic reprogramming of myeloid cells following endogenous or exogenous stimulation, resulting in enhanced inflammation to subsequent stimuli. Trained immunity phenotypes have now been reported for other immune and non-immune cells. Here, we provide a novel perspective on the putative role of trained immunity in mediating the adverse cardiovascular effects of obesity and highlight potential translational pathways.

    Heritability estimates for 361 blood metabolites across 40 genome-wide association studies
    Hagenbeek, Fiona A. ; Pool, René ; Dongen, Jenny van; Draisma, Harmen H.M. ; Hottenga, Jouke Jan ; Willemsen, Gonneke ; Abdellaoui, Abdel ; Fedko, Iryna O. ; Braber, Anouk den; Visser, Pieter Jelle ; Geus, Eco J.C.N. de; Willems van Dijk, Ko ; Verhoeven, Aswin ; Suchiman, H.E. ; Beekman, Marian ; Slagboom, Eline P. ; Duijn, Cornelia M. van; Barkey Wolf, J.J.H. ; Cats, D. ; Amin, N. ; Beulens, J.W. ; Bom, J.A. van der; Bomer, N. ; Demirkan, A. ; Hilten, J.A. van; Meessen, J.M.T.A. ; Moed, M.H. ; Fu, J. ; Onderwater, G.L.J. ; Rutters, F. ; So-Osman, C. ; Flier, W.M. van der; Heijden, A.A.W.A. van der; Spek, A. van der; Asselbergs, F.W. ; Boersma, E. ; Elders, P.M. ; Geleijnse, J.M. ; Ikram, M.A. ; Kloppenburg, M. ; Meulenbelt, I. ; Mooijaart, S.P. ; Nelissen, R.G.H.H. ; Netea, M.G. ; Penninx, B.W.J.H. ; Stehouwer, C.D.A. ; Teunissen, C.E. ; Terwindt, G.M. ; Jukema, J.W. ; Reinders, M.J.T. - \ 2020
    Nature Communications 11 (2020)1. - ISSN 2041-1723

    Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2 total), and the proportion of heritability captured by known metabolite loci (h2 Metabolite-hits) for 309 lipids and 52 organic acids. Our study reveals significant differences in h2 Metabolite-hits among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation have higher h2 Metabolite-hits estimates than phosphatidylcholines with low degrees of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes.

    Deletion of haematopoietic Dectin-2 or CARD9 does not protect from atherosclerosis development under hyperglycaemic conditions
    Thiem, Kathrin ; Hoeke, Geerte ; Zhou, Enchen ; Hijmans, Anneke ; Houben, Tom ; Boels, Margien G. ; Mol, Isabel M. ; Lutgens, Esther ; Shiri-Sverdlov, Ronit ; Bussink, Johan ; Kanneganti, Thirumala D. ; Boon, Mariëtte R. ; Stienstra, Rinke ; Tack, Cees J. ; Rensen, Patrick C.N. ; Netea, Mihai G. ; Berbée, Jimmy F.P. ; Diepen, Janna A. van - \ 2020
    Diabetes & Vascular Disease Research 17 (2020)1. - ISSN 1479-1641 - p. 1 - 12.
    Atherosclerosis - C-type lectin receptors - CARD9 - Dectin-2 - hyperglycaemia - inflammation - monocytes/macrophages

    Background: C-type lectin receptors, including Dectin-2, are pattern recognition receptors on monocytes and macrophages that mainly recognize sugars and sugar-like structures present on fungi. Activation of C-type lectin receptors induces downstream CARD9 signalling, leading to the production of cytokines. We hypothesized that under hyperglycaemic conditions, as is the case in diabetes mellitus, glycosylated protein (sugar-like) structures activate C-type lectin receptors, leading to immune cell activation and increased atherosclerosis development. Methods: Low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with bone marrow from control wild-type, Dectin-2−/− or Card9−/− mice. After 6 weeks of recovery, mice received streptozotocin injections (50 mg/g BW; 5 days) to induce hyperglycaemia. After an additional 2 weeks, mice were fed a Western-type diet (0.1% cholesterol) for 10 weeks. Results and Conclusion: Deletion of haematopoietic Dectin-2 reduced the number of circulating Ly6Chi monocytes, increased pro-inflammatory cytokine production, but did not affect atherosclerosis development. Deletion of haematopoietic CARD9 tended to reduce macrophage and collagen content in atherosclerotic lesions, again without influencing the lesion size. Deletion of haematopoietic Dectin-2 did not influence atherosclerosis development under hyperglycaemic conditions, despite some minor effects on inflammation. Deletion of haematopoietic CARD9 induced minor alterations in plaque composition under hyperglycaemic conditions, without affecting lesion size.

    Akkermansia muciniphila Exerts Lipid-Lowering and Immunomodulatory Effects without Affecting Neointima Formation in Hyperlipidemic APOE*3-Leiden.CETP Mice
    Katiraei, Saeed ; Vries, Margreet R. de; Costain, Alice H. ; Thiem, Kathrin ; Hoving, Lisa R. ; Diepen, Janna A. van; Smits, Hermelijn H. ; Bouter, Kristien E. ; Rensen, Patrick C.N. ; Quax, Paul H.A. ; Nieuwdorp, Max ; Netea, Mihai G. ; Vos, Willem M. de; Cani, Patrice D. ; Belzer, Clara ; Dijk, Ko Willems van; Berbée, Jimmy F.P. ; Harmelen, Vanessa van - \ 2020
    Molecular Nutrition & Food Research 64 (2020)15. - ISSN 1613-4125 - 10 p.
    Akkermansia muciniphila - atherosclerosis - immunity - lipid metabolism - mesenteric lymph nodes

    Scope: Akkermansia muciniphila (A. muciniphila) is an intestinal commensal with anti-inflammatory properties both in the intestine and other organs. The aim is to investigate the effects of oral administration of A. muciniphila on lipid metabolism, immunity, and cuff-induced neointima formation in hyperlipidemic APOE*3-Leiden (E3L).CETP mice. Methods and results: Hyperlipidemic male E3L.CETP mice are daily treated with 2 × 108 CFU A. muciniphila by oral gavage for 4 weeks and the effects are determined on plasma lipid levels, immune parameters, and cuff-induced neointima formation and composition. A. muciniphila administration lowers body weight and plasma total cholesterol and triglycerides levels. A. muciniphila influences the immune cell composition in mesenteric lymph nodes, as evident from an increased total B cell population, while reducing the total T cell and neutrophil populations. Importantly, A. muciniphila reduces the expression of the activation markers MHCII on dendritic cells and CD86 on B cells. A. muciniphila also increases whole blood ex vivo lipopolysaccharide-stimulated IL-10 release. Finally, although treatment with A. muciniphila improves lipid metabolism and immunity, it does not affect neointima formation or composition. Conclusions: Four weeks of treatment with A. muciniphila exerts lipid-lowering and immunomodulatory effects, which are insufficient to inhibit neointima formation in hyperlipidemic E3L.CETP mice.

    Metformin Alters Human Host Responses to Mycobacterium tuberculosis in Healthy Subjects
    Lachmandas, Ekta ; Eckold, Clare ; Böhme, Julia ; Koeken, Valerie A.C.M. ; Marzuki, Mardiana Binte ; Blok, Bastiaan ; Arts, Rob J.W. ; Chen, Jinmiao ; Teng, Karen W.W. ; Ratter, Jacqueline ; Smolders, Elise J. ; Heuvel, Corina Van den; Stienstra, Rinke ; Dockrell, Hazel M. ; Newell, Evan ; Netea, Mihai G. ; Singhal, Amit ; Cliff, Jacqueline M. ; Crevel, Reinout Van - \ 2019
    The Journal of Infectious Diseases 220 (2019)1. - ISSN 0022-1899 - p. 139 - 150.
    antimycobacterial mechanisms - gene transcription - host-directed therapy - Metformin - tuberculosis

    BACKGROUND: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis. METHODS: We investigated in vitro and in vivo effects of metformin in humans. RESULTS: Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1β but increased phagocytosis activity and reactive oxygen species production. CONCLUSION: Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis.

    Deletion of hematopoietic Dectin-2 or CARD9 does not protect against atherosclerotic plaque formation in hyperlipidemic mice
    Thiem, Kathrin ; Hoeke, Geerte ; Berg, Susan van den; Hijmans, Anneke ; Jacobs, Cor W.M. ; Zhou, Enchen ; Mol, Isabel M. ; Mouktaroudi, Maria ; Bussink, Johan ; Kanneganti, Thirumala D. ; Lutgens, Esther ; Stienstra, Rinke ; Tack, Cees J. ; Netea, Mihai G. ; Rensen, Patrick C.N. ; Berbée, Jimmy F.P. ; Diepen, Janna A. van - \ 2019
    Scientific Reports 9 (2019)1. - ISSN 2045-2322

    Inflammatory reactions activated by pattern recognition receptors (PRRs) on the membrane of innate immune cells play an important role in atherosclerosis. Whether the PRRs of the C-type lectin receptor (CLR) family including Dectin-2 may be involved in the pathogenesis of atherosclerosis remains largely unknown. Recently, the CLR-adaptor molecule caspase recruitment domain family member 9 (CARD9) has been suggested to play a role in cardiovascular pathologies as it provides the link between CLR activation and transcription of inflammatory cytokines as well as immune cell recruitment. We therefore evaluated whether hematopoietic deletion of Dectin-2 or CARD9 reduces inflammation and atherosclerosis development. Low-density lipoprotein receptor (Ldlr)-knockout mice were transplanted with bone marrow from wild-type, Dectin-2- or Card9-knockout mice and fed a Western-type diet containing 0.1% (w/w) cholesterol. After 10 weeks, lipid and inflammatory parameters were measured and atherosclerosis development was determined. Deletion of hematopoietic Dectin-2 or CARD9 did not influence plasma triglyceride and cholesterol levels. Deletion of hematopoietic Dectin-2 did not affect atherosclerotic lesion area, immune cell composition, ex vivo cytokine secretion by peritoneal cells or bone marrow derived macrophages. Unexpectedly, deletion of hematopoietic CARD9 increased atherosclerotic lesion formation and lesion severity. Deletion of hematopoietic CARD9 did also not influence circulating immune cell composition and peripheral cytokine secretion. Besides a tendency to a reduced macrophage content within these lesions, plasma MCP-1 levels decreased upon WTD feeding. Deletion of hematopoietic Dectin-2 did not influence atherosclerosis development in hyperlipidemic mice. The absence of CARD9 unexpectedly increased atherosclerotic lesion size and severity, suggesting that the presence of CARD9 may protect against initiation of atherosclerosis development.

    Effects of oral butyrate supplementation on inflammatory potential of circulating peripheral blood mononuclear cells in healthy and obese males
    Cleophas, Maartje C.P. ; Ratter, Jacqueline M. ; Bekkering, Siroon ; Quintin, Jessica ; Schraa, Kiki ; Stroes, Erik S. ; Netea, Mihai G. ; Joosten, Leo A.B. - \ 2019
    Scientific Reports 9 (2019). - ISSN 2045-2322

    Sodium butyrate is well-known for its immune-modulatory properties. Studies until now only focused on the in vitro effects of butyrate or assessed local effects in the gut upon butyrate administration. In this trial, we studied the systemic anti-inflammatory effects induced by sodium butyrate supplementation in humans. Nine healthy (Lean) and ten obese (metabolic syndrome group, MetSyn) males were given 4 grams sodium butyrate daily for 4 weeks. PBMCs were isolated before and after supplementation for direct stimulation experiments and induction of trained immunity by oxidized low-density lipoprotein (oxLDL), β-glucan, or Bacillus Calmette-Guérin vaccine (BCG). Butyrate supplementation moderately affected some of the cytokine responses in the MetSyn group. In the direct stimulation setup, effects of butyrate supplementation were limited. Interestingly, butyrate supplementation decreased oxLDL-induced trained immunity in the MetSyn group for LPS-induced IL-6 responses and Pam3CSK4-induced TNF-α responses. Induction of trained immunity by β-glucan was decreased by butyrate in the MetSyn group for Pam3CSK4-induced IL-10 production. In this study, while having only limited effects on the direct stimulation of cytokine production, butyrate supplementation significantly affected trained immunity in monocytes of obese individuals with metabolic complications. Therefore, oral butyrate supplementation may be beneficial in reducing the overall inflammatory status of circulating monocytes in patients with metabolic syndrome.

    Firing Up Glycolysis : BCG Vaccination Effects on Type 1 Diabetes Mellitus
    Stienstra, Rinke ; Netea, Mihai G. - \ 2018
    Trends in Endocrinology & Metabolism 29 (2018)12. - ISSN 1043-2760 - p. 813 - 814.

    In addition to the impact of Bacillus Calmette–Guerin (BCG) vaccination on antimicrobial host defence, a novel study reveals beneficial effects on glycaemic control in patients with long-standing type 1 diabetes mellitus (T1DM). These effects are ascribed to an accelerated glucose consumption in immune cells due to increased glycolysis and reduced oxidative phosphorylation.

    Induction of trained innate immunity in human monocytes by bovine milk and milk-derived immunoglobulin G
    Splunter, Marloes van; Osch, Thijs L.J. van; Brugman, Sylvia ; Savelkoul, Huub F.J. ; Joosten, Leo A.B. ; Netea, Mihai G. ; Neerven, R.J.J. van - \ 2018
    Nutrients 10 (2018)10. - ISSN 2072-6643
    Bovine IgG - Bovine lactoferrin - Dietary compounds - Innate immune memory - Monocytes - Raw bovine milk - Trained immunity

    Innate immune memory, also termed “trained immunity” in vertebrates, has been recently described in a large variety of plants and animals. In most cases, trained innate immunity is induced by pathogens or pathogen-associated molecular patterns (PAMPs), and is associated with long-term epigenetic, metabolic, and functional reprogramming. Interestingly, recent findings indicate that food components can mimic PAMPs effects and induce trained immunity. The aim of this study was to investigate whether bovine milk or its components can induce trained immunity in human monocytes. To this aim, monocytes were exposed for 24 h to β-glucan, Toll-like receptor (TLR)-ligands, bovine milk, milk fractions, bovine lactoferrin (bLF), and bovine Immunoglobulin G (bIgG). After washing away the stimulus and a resting period of five days, the cells were re-stimulated with TLR ligands and Tumor necrosis factor (TNF-) and interleukin (IL)-6 production was measured. Training with β-glucan resulted in higher cytokine production after TLR1/2, TLR4, and TLR7/8 stimulation. When monocytes trained with raw milk were re-stimulated with TLR1/2 ligand Pam3CSK4, trained cells produced more IL-6 compared to non-trained cells. Training with bIgG resulted in higher cytokine production after TLR4 and TLR7/8 stimulation. These results show that bovine milk and bIgG can induce trained immunity in human monocytes. This confirms the hypothesis that diet components can influence the long-term responsiveness of the innate immune system.

    Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis
    Lachmandas, Ekta ; Rios-Miguel, Ana B. ; Koeken, Valerie A.C.M. ; Pasch, Eva van der; Kumar, Vinod ; Matzaraki, Vasiliki ; Li, Yang ; Oosting, Marije ; Joosten, Leo A.B. ; Notebaart, Richard A. ; Noursadeghi, Mahdad ; Netea, Mihai G. ; Crevel, Reinout van; Pollara, Gabriele - \ 2018
    The Journal of Infectious Diseases 218 (2018)1. - ISSN 0022-1899 - p. 165 - 170.
    cytokines - functional genomics - human challenge model - immune response - immunometabolism - metabolism - microarrays - transcriptomics - tuberculosis

    Cellular metabolism can influence host immune responses to Mycobacterium tuberculosis. Using a systems biology approach, differential expression of 292 metabolic genes involved in glycolysis, glutathione, pyrimidine, and inositol phosphate pathways was evident at the site of a human tuberculin skin test challenge in patients with active tuberculosis infection. For 28 metabolic genes, we identified single nucleotide polymorphisms that were trans-acting for in vitro cytokine responses to M. tuberculosis stimulation, including glutathione and pyrimidine metabolism genes that alter production of Th1 and Th17 cytokines. Our findings identify novel therapeutic targets in host metabolism that may shape protective immunity to tuberculosis.

    Environmental Signals Influencing Myeloid Cell Metabolism and Function in Diabetes
    Ratter, Jacqueline M. ; Tack, Cees J. ; Netea, Mihai G. ; Stienstra, Rinke - \ 2018
    Trends in Endocrinology & Metabolism 29 (2018)7. - ISSN 1043-2760 - p. 468 - 480.
    diabetes - immunometabolism - inflammation - macrophages

    The environment induces metabolic reprogramming of immune cells via specific signaling pathways. Recent studies have revealed that changes in cell metabolism affect key immune cell functions including cytokine production and migration. In diabetes, these functions are either insufficiently or excessively activated, translating into diabetes-associated complications, including increased susceptibility to infection and accelerated cardiovascular disease. Diabetes alters the abundance of environmental signals, including glucose, insulin, and lipids. Subsequently, changes in environmental signals drive metabolic reprogramming, impair immune cell function, and ultimately contribute to diabetes-associated complications. We review here recent studies on changes in innate immune cell metabolism, especially in myeloid cells, that are driven by environmental signals relevant to diabetes, and discuss therapeutic perspectives of targeting metabolism of immune cells in diabetes.

    A role for TLR10 in obesity and adipose tissue morphology
    Boutens, Lily ; Mirea, Andreea Manuela ; Munckhof, Inge van den; Doppenberg-Oosting, Marije ; Jaeger, Martin ; Hijmans, Anneke ; Netea, Mihai G. ; Joosten, Leo A.B. ; Stienstra, Rinke - \ 2018
    Cytokine 108 (2018). - ISSN 1043-4666 - p. 205 - 212.
    Adipose tissue - Inflammation - Obesity - SNPs - TLR10
    Toll like receptors (TLRs) are expressed in adipose tissue and promote adipose tissue inflammation during obesity. Recently, anti-inflammatory properties have been attributed to TLR10 in myeloid cells, the only member of the TLR family with inhibitory activity. In order to assess whether TLR10-induced inhibition of inflammation may be protective during the development of obesity and metabolic abnormalities we used transgenic human TLR10 mice (hTLR10tg) and wild type (WT) controls on a C57B6J background. HFD-feeding enhanced TLR10 expression in the adipose tissue, and HFD-fed hTLR10tg mice displayed reduced adipocyte size, adipose tissue weight, and a trend toward lower plasma insulin levels compared to WT mice. In humans, obese individuals with polymorphisms in the TLR10 gene displayed reduced macrophage infiltration in the adipose tissue accompanied by a trend to lower leptin levels and higher adiponectin levels in plasma. In healthy individuals with the same polymorphisms in the TLR10 gene we did not observe any difference in plasma concentrations of leptin and adiponectin. We conclude that TLR10 impacts adipose tissue morphology in obesity. Larger studies in humans are warranted to assess its potential value as therapeutic target in metabolic syndrome and type 2 diabetes.
    Effect of vegan fecal microbiota transplantation on carnitine- and choline-derived trimethylamine-N-oxide production and vascular inflammation in patients with metabolic syndrome
    Smits, Loek P. ; Kootte, Ruud S. ; Levin, Evgeni ; Prodan, Andrei ; Fuentes, Susana ; Zoetendal, Erwin G. ; Wang, Zeneng ; Levison, Bruce S. ; Cleophas, Maartje C.P. ; Kemper, E.M. ; Dallinga-Thie, Geesje M. ; Groen, Albert K. ; Joosten, Leo A.B. ; Netea, Mihai G. ; Stroes, Erik S.G. ; Vos, Willem M. de; Hazen, Stanley L. ; Nieuwdorp, Max - \ 2018
    Journal of the American Heart Association 7 (2018)7. - ISSN 2047-9980
    Atherosclerosis - Cardiovascular disease - Cardiovascular imaging - Inflammation - Metabolism
    Background--Intestinal microbiota have been found to be linked to cardiovascular disease via conversion of the dietary compounds choline and carnitine to the atherogenic metabolite TMAO (trimethylamine-N-oxide). Specifically, a vegan diet was associated with decreased plasma TMAO levels and nearly absent TMAO production on carnitine challenge. Methods and Results--We performed a double-blind randomized controlled pilot study in which 20 male metabolic syndrome patients were randomized to single lean vegan-donor or autologous fecal microbiota transplantation. At baseline and 2 weeks thereafter, we determined the ability to produce TMAO from d6-choline and d3-carnitine (eg, labeled and unlabeled TMAO in plasma and 24-hour urine after oral ingestion of 250 mg of both isotope-labeled precursor nutrients), and fecal samples were collected for analysis of microbiota composition. 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans of the abdominal aorta, as well as ex vivo peripheral blood mononuclear cell cytokine production assays, were performed. At baseline, fecal microbiota composition differed significantly between vegans and metabolic syndrome patients. With vegan-donor fecal microbiota transplantation, intestinal microbiota composition in metabolic syndrome patients, as monitored by global fecal microbial community structure, changed toward a vegan profile in some of the patients; however, no functional effects from vegan-donor fecal microbiota transplantation were seen on TMAO production, abdominal aortic 18Ffluorodeoxyglucose uptake, or ex vivo cytokine production from peripheral blood mononuclear cells. Conclusions--Single lean vegan-donor fecal microbiota transplantation in metabolic syndrome patients resulted in detectable changes in intestinal microbiota composition but failed to elicit changes in TMAO production capacity or parameters related to vascular inflammation.
    Understanding macrophage activation in the adipose tissue: at the crossroads of immunology and metabolism
    Boutens, Lily - \ 2018
    Wageningen University. Promotor(en): A.H. Kersten; M.G. Netea, co-promotor(en): R. Stienstra. - Wageningen : Wageningen University - ISBN 9789463438896 - 240

    Macrophages and their monocyte precursors continuously patrol the bloodstream and tissues, ready to eliminate unwelcome visitors such as pathogens or foreign particles. Tissue-resident macrophages are crucial during development and for maintaining tissue homeostasis as well. The engulfment of dying or damaged tissue cells, a process called efferocytosis, is a central part of their role to maintain homeostasis, yet is accompanied by several other tissue-tailored functions. Accordingly, macrophages display great plasticity by adopting unique phenotypes to fulfil tissue-specific needs.

    This thesis is particularly devoted to macrophages residing in the adipose tissue. In lean conditions adipose tissue macrophages (ATMs) promote tissue and whole-body homeostasis by buffering lipids released by adipocytes and removing dead or damaged cells, and ensure tissue dynamics by promoting angiogenesis, adipogenesis, and extracellular matrix remodelling. Obese adipose tissue, however, is characterized by low-grade chronic inflammation reflective of homeostatic imbalance. Given their pivotal role for maintaining homeostasis in lean conditions, ATMs are considered key players in the development of adipose tissue inflammation during obesity. Indeed, during obesity ATMs sharply increase in number while simultaneously gaining a pro-inflammatory trait. This pro-inflammatory activation of ATMs is thought to importantly link obesity to the development of insulin resistance and, ultimately, Type 2 Diabetes.

    Notwithstanding the considerable progress made, the underlying causes of macrophage activation and phenotypical and functional characteristics of ATMs in obese adipose tissue have not yet been fully unravelled. In this thesis, we have investigated various aspects of activation of macrophage and their monocyte precursors. First, we have examined metabolic reprogramming in monocytes stimulated with various pathogenic stimuli (Chapter 2). This research adds to the growing evidence of intracellular metabolism as fundamental driver of immune cell functioning. In contrast to the majority of studies in the field that have focussed on one single stimulant, we have carefully evaluated intracellular metabolism upon activation with different pathogenic stimuli, including whole pathogen lysates and isolated Toll-like receptor (TLR) ligands. In line with the current paradigm, we found glycolysis to be a general characteristic of monocyte activation irrespective of the present stimulus. Interestingly, however, in contrast to the current paradigm, oxidative phosphorylation (OXPHOS), the alternative route for ATP production that occupies mitochondria, was found to be enhanced by most pathogenic stimuli as well. In fact, the most commonly used stimulant for activating monocytes and macrophages, being lipopolysaccharide (LPS), appeared unique in aggravating mitochondrial metabolism. Importantly, such stimulus-specific metabolic reprogramming appeared to have functional consequences, that we evaluated by comparing the two different TLR-ligands LPS (TLR4 ligand) and Pam3CysSK4 (P3C: TLR2 ligand). While glycolysis contributed to cytokine release by both LPS and P3C, OXPHOS only contributed to cytokine production in P3C-stimulated monocytes. Moreover, phagocytosis appeared to rely on OXPHOS but not glycolysis in monocytes stimulated with P3C. Probably consequential to their reduced mitochondrial activity, LPS-stimulated monocytes displayed low phagocytic capacity. Together these findings are suggestive of stimulus-tailored metabolic rearrangements fuelling functional output of monocytes.

    After reviewing various aspects of ATMs in Chapter 3 – including their origin, activation and function in obese versus lean conditions – we examined metabolic rearrangements in ATMs, and evaluated their contribution to the pro-inflammatory ATM trait apparent in obese adipose tissue (Chapter 4). Not surprisingly given the rather challenging environment provided by obese adipose tissue, ATMs were found to be strongly metabolically activated during obesity illustrated by enhanced activation of both glycolysis and OXPHOS. Interestingly, this metabolic activation appeared to be specific for ATMs, and was not manifested in macrophages isolated from the peritoneum of obese versus lean mice. In line with recent studies, we showed that both the metabolic and inflammatory trait of ATMs was pronouncedly different from that displayed by classically (LPS-)activated macrophages. Indeed, the ATM phenotype appeared dose-dependently induced by adipose tissue-derived factors. Using metabolic inhibitors, we identified various metabolic routes including fatty acid oxidation, glycolysis and glutaminolysis to contribute to cytokine release by ATMs isolated from lean mice. Glycolysis, however, contributed the most to cytokine production and was responsible for the increased release of inflammatory cytokines by ATMs from obese mice. Unexpectedly, however, HIF-1α, a key regulator of glycolysis and inflammatory activation, appeared not to be critically involved in the development of a pro-inflammatory ATM trait during obesity.

    Because lipids most likely play a central role in shaping the ATM phenotype, we evaluated the role of triglycerides (TGs) versus free fatty acids (FFAs) as driver of pro-inflammatory activation of ATMs in Chapter 5. First we confirmed lipid handling to be a fundamental characteristic of ATMs by showing that ATMs, but not other tissue macrophages or circulating monocytes from humans and mice, display enhanced expression of genes involved in lipid uptake and processing. This associated with increased expression of ER stress markers and inflammatory activation of macrophages, pointing to a relation between lipid loading and inflammatory activation of ATMs. Interestingly, both lipoprotein lipase (Lpl), that breaks down extracellular TGs into FAs that can be taken up, and its endogenous inhibitor angiopoietin-like 4 (Angptl4) were upregulated in macrophages in an adipose tissue environment, suggestive of the presence of a negative feedback mechanism to limit LPL activity and thus excessive uptake of FAs from TGs. Indeed, we observed ANGPTL4 to inhibit inflammatory activation of macrophages in an adipose tissue environment. Intriguingly, however, reduced inflammatory activation of Angptl4 knock-out macrophages in an adipose tissue environment appeared to be independent of lipid loading which most likely occurred through uptake of FFAs rather than TGs.

    In Chapter 6, we zoomed into a role for ATMs in efferoctysis of dead adipocytes, that may impose an important source of lipids for ATMs. Indeed, we found profound transcriptional regulation of the efferocytic machinery in ATMs isolated from obese versus lean adipose tissue accompanied by increased expression of genes involved in lipid handling and processing of lipid-derivatives. In vitro, dead adipocytes were readily taken up by macrophages and induced the expression of various genes involved in lipid handling, similar to what we found in ATMs in vivo. Interestingly, macrophages part of obese adipose tissue display pronounced down-regulation of Interferon (IFN)-signalling, whereas effective efferocytosis in vitro was characterized by enhanced IFN signalling. Accordingly, our data are suggestive of a link between impaired IFN signalling and dysfunctional, pro-inflammatory ATMs in obese adipose tissue.

    Lastly, in Chapter 7 we have evaluated a role for TLR10, the sole anti-inflammatory TLR family member, in adipose tissue of humans and mice. Because mice do not express functional TLR10, we fed mice expressing human TLR10 a high-fat diet for 16 weeks. Unexpectedly, TLR10 did not attenuate the development of adipose tissue inflammation during obesity. Interestingly, however, mice carrying human TLR10 had reduced adipose tissue weight and adipocyte size, suggestive of a role for TLR10 in adiposity. In humans, obese but not lean individuals carrying single nucleotide polymorphisms (SNPs) in TLR10 had or tended to have lower circulating leptin and macrophage numbers in the adipose tissue, reflective of a role for TLR10 in the adipose tissue at states of low-grade chronic inflammation specifically.

    In conclusion, we have revealed macrophage metabolic reprogramming to be stimulus-driven and location-specific and crucial for fuelling functional output in line with specific environmental demands. In the adipose tissue, lipid handling is central to macrophage functioning, yet ATMs appear to be overwhelmed by lipids during obesity. From a therapeutic point of view, we propose stimulation of FA oxidation to support ATM functioning according to increasing demands of the obese adipose tissue environment, while simultaneously driving them away from glycolysis that appeared to critically underlie their pro-inflammatory trait. Future studies, however, are warranted to clarify the therapeutic potential of raising mitochondrial FA oxidation in ATMs of obese individuals.

    Cerebral tryptophan metabolism and outcome of tuberculous meningitis : An observational cohort study
    Laarhoven, Arjan van; Dian, Sofiati ; Aguirre-Gamboa, Raúl ; Avila-Pacheco, Julian ; Ricaño-Ponce, Isis ; Ruesen, Carolien ; Annisa, Jessi ; Koeken, Valerie A.C.M. ; Chaidir, Lidya ; Li, Yang ; Achmad, Tri Hanggono ; Joosten, Leo A.B. ; Notebaart, Richard A. ; Ruslami, Rovina ; Netea, Mihai G. ; Verbeek, Marcel M. ; Alisjahbana, Bachti ; Kumar, Vinod ; Clish, Clary B. ; Ganiem, A.R. ; Crevel, Reinout van - \ 2018
    The Lancet Infectious Diseases 18 (2018)5. - ISSN 1473-3099 - p. 526 - 535.
    Background: Immunopathology contributes to the high mortality of tuberculous meningitis, but the biological pathways involved are mostly unknown. We aimed to compare cerebrospinal fluid (CSF) and serum metabolomes of patients with tuberculous meningitis with that of controls without tuberculous meningitis, and assess the link between metabolite concentrations and mortality. Methods: In this observational cohort study at the Hasan Sadikin Hospital (Bandung, Indonesia) we measured 425 metabolites using liquid chromatography-mass spectrometry in CSF and serum from 33 HIV-negative Indonesian patients with confirmed or probable tuberculous meningitis and 22 control participants with complete clinical data between March 12, 2009, and Oct 27, 2013. Associations of metabolite concentrations with survival were validated in a second cohort of 101 patients from the same centre. Genome-wide single nucleotide polymorphism typing was used to identify tryptophan quantitative trait loci, which were used for survival analysis in a third cohort of 285 patients. Findings: Concentrations of 250 (70%) of 351 metabolites detected in CSF were higher in patients with tuberculous meningitis than in controls, especially in those who died during follow-up. Only five (1%) of the 390 metobolites detected in serum differed between patients with tuberculous meningitis and controls. CSF tryptophan concentrations showed a pattern different from most other CSF metabolites; concentrations were lower in patients who survived compared with patients who died (9-times) and to controls (31-times). The association of low CSF tryptophan with patient survival was confirmed in the validation cohort (hazard ratio 0·73; 95% CI 0·64-0·83; p<0·0001; per each halving). 11 genetic loci predictive for CSF tryptophan concentrations in tuberculous meningitis were identified (p<0·00001). These quantitative trait loci predicted survival in a third cohort of 285 HIV-negative patients in a prognostic index including age and sex, also after correction for possible confounders (p=0·0083). Interpretation: Cerebral tryptophan metabolism, which is known to affect Mycobacterium tuberculosis growth and CNS inflammation, is important for the outcome of tuberculous meningitis. CSF tryptophan concentrations in tuberculous meningitis are under strong genetic influence, probably contributing to the variable outcomes of tuberculous meningitis. Interventions targeting tryptophan metabolism could improve outcomes of tuberculous meningitis. Funding: Royal Dutch Academy of Arts and Sciences; Netherlands Foundation for Scientific Research; Radboud University; National Academy of Sciences; Ministry of Research, Technology, and Higher Education, Indonesia; European Research Council; and PEER-Health.
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