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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    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.

    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.

    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.

    Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis
    Domínguez-Andrés, Jorge ; Arts, Rob J.W. ; Horst, Rob ter; Gresnigt, Mark S. ; Smeekens, Sanne P. ; Ratter, Jacqueline M. ; Lachmandas, Ekta ; Boutens, Lily ; Veerdonk, Frank L. van de; Joosten, Leo A.B. ; Notebaart, Richard A. ; Ardavín, Carlos ; Netea, Mihai G. - \ 2017
    PLoS Pathogens 13 (2017)9. - ISSN 1553-7366 - 23 p.

    Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyphae was accompanied by metabolic rewiring induced through C-type lectin-signaling pathways. We describe that the innate immune responses against Candida yeast are energy-demanding processes that lead to the mobilization of intracellular metabolite pools and require induction of glucose metabolism, oxidative phosphorylation and glutaminolysis, while responses to hyphae primarily rely on glycolysis. Experimental models of systemic candidiasis models validated a central role for glucose metabolism in anti-Candida immunity, as the impairment of glycolysis led to increased susceptibility in mice. Collectively, these data highlight the importance of understanding the complex network of metabolic responses triggered during infections, and unveil new potential targets for therapeutic approaches against fungal diseases.

    Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity
    Arts, Rob J.W. ; Novakovic, Boris ; Horst, Rob ter; Carvalho, Agostinho ; Bekkering, Siroon ; Lachmandas, Ekta ; Rodrigues, Fernando ; Silvestre, Ricardo ; Cheng, Shih Chin ; Wang, Shuang Yin ; Habibi, Ehsan ; Gonçalves, Luís G. ; Mesquita, Inês ; Cunha, Cristina ; Laarhoven, Arjan van; Veerdonk, Frank L. van de; Williams, David L. ; Meer, Jos W.M. van der; Logie, Colin ; O'Neill, Luke A. ; Dinarello, Charles A. ; Riksen, Niels P. ; Crevel, Reinout van; Clish, Clary ; Notebaart, Richard A. ; Joosten, Leo A.B. ; Stunnenberg, Hendrik G. ; Xavier, Ramnik J. ; Netea, Mihai G. - \ 2016
    Cell Metabolism 24 (2016)6. - ISSN 1550-4131 - p. 807 - 819.
    cholesterol metabolism - epigenetics - glutamine metabolism - glycolysis - trained immunity

    Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.

    Different pathogenic stimuli induce specific metabolic rewiring in human monocytes
    Lachmandas, Ekta ; Boutens, Lily ; Ratter, Jacqueline ; Hijmans, Anneke ; Hooiveld, Guido ; Crevel, Reinout van; Netea, Mihai ; Stienstra, Rinke - \ 2016
    Wageningen University
    Homo sapiens - GSE78699 - Homo sapiens - GSE78699 - PRJNA313233
    Recent studies have demonstrated that upon encountering a pathogenic stimulus, robust metabolic rewiring of immune cells occurs. A switch away from oxidative phosphorylation to glycolysis, even in the presence of sufficient amounts of oxygen (akin the Warburg effect), is typically observed in activated innate and adaptive immune cells and is thought to accommodate adequate inflammatory responses. However, whether the Warburg effect is a general phenomenon applicable in human monocytes exposed to different pathogenic stimuli is unknown. Our results using human monocytes from healthy donors demonstrate that the Warburg effect only holds true for TLR4 activated cells. Although activation of other TLRs leads to an increase in glycolysis, no reduction or even an enhancement in oxidative phosphorylation is observed. Moreover, specific metabolic rewiring occurs in TLR4 vs. TLR2 stimulated cells characterized by altered gene expression profiles of pathways related to metabolism, changes in spare respiratory capacity of the cells and differential regulation of mitochondrial enzyme activity. Similarly, results from ex vivo and in vivo studies demonstrate metabolic rewiring of immune cells that is highly dependent on the type of pathogenic stimulus. Although the Warburg effect is observed in human monocytes after TLR4 activation, we propose that this typical metabolic response is not applicable to other inflammatory signalling routes including TLR2 in human monocytes. Instead, each pathogenic stimulus and subsequently activated inflammatory signalling cascade induces specific metabolic rewiring of the immune cell to accommodate an appropriate response.
    Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes
    Lachmandas, Ekta ; Boutens, Lily ; Ratter, Jacqueline M. ; Hijmans, Anneke ; Hooiveld, Guido J. ; Joosten, Leo A.B. ; Rodenburg, Richard J. ; Fransen, Jack A.M. ; Houtkooper, Riekelt H. ; Crevel, R. van; Netea, Mihai G. ; Stienstra, R. - \ 2016
    Nature Microbiology 2 (2016). - ISSN 2058-5276

    Microbial stimuli such as lipopolysaccharide (LPS) induce robust metabolic rewiring in immune cells known as the Warburg effect. It is unknown whether this increase in glycolysis and decrease in oxidative phosphorylation (OXPHOS) is a general characteristic of monocytes that have encountered a pathogen. Using CD14+ monocytes from healthy donors, we demonstrated that most microbial stimuli increased glycolysis, but that only stimulation of Toll-like receptor (TLR) 4 with LPS led to a decrease in OXPHOS. Instead, activation of other TLRs, such as TLR2 activation by Pam3CysSK4 (P3C), increased oxygen consumption and mitochondrial enzyme activity. Transcriptome and metabolome analysis of monocytes stimulated with P3C versus LPS confirmed the divergent metabolic responses between both stimuli, and revealed significant differences in the tricarboxylic acid cycle, OXPHOS and lipid metabolism pathways following stimulation of monocytes with P3C versus LPS. At a functional level, pharmacological inhibition of complex I of the mitochondrial electron transport chain diminished cytokine production and phagocytosis in P3C- but not LPS-stimulated monocytes. Thus, unlike LPS, complex microbial stimuli and the TLR2 ligand P3C induce a specific pattern of metabolic rewiring that involves upregulation of both glycolysis and OXPHOS, which enables activation of host defence mechanisms such as cytokine production and phagocytosis.

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