50 results on '"Arts, Rob J."'
Search Results
2. Anticytokine Autoantibodies in Infectious Diseases: A Practical Overview.
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Arts, Rob J. W., Janssen, Nico A. F., and van de Veerdonk, Frank L.
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AUTOANTIBODIES , *COMMUNICABLE diseases , *IMMUNOSPECIFICITY , *AUTOIMMUNITY , *IMMUNOGLOBULINS , *FC receptors - Abstract
Anticytokine autoantibodies (ACAAs) are a fascinating group of antibodies that have gained more and more attention in the field of autoimmunity and secondary immunodeficiencies over the years. Some of these antibodies are characterized by their ability to target and neutralize specific cytokines. ACAAs can play a role in the susceptibility to several infectious diseases, and their infectious manifestations depending on which specific immunological pathway is affected. In this review, we will give an outline per infection in which ACAAs might play a role and whether additional immunomodulatory treatment next to antimicrobial treatment can be considered. Finally, we describe the areas for future research on ACAAs. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Outcomes of controlled human malaria infection after BCG vaccination
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Walk, Jona, de Bree, L. Charlotte J., Graumans, Wouter, Stoter, Rianne, van Gemert, Geert-Jan, van de Vegte-Bolmer, Marga, Teelen, Karina, Hermsen, Cornelus C., Arts, Rob J. W., Behet, Marije C., Keramati, Farid, Moorlag, Simone J. C. F. M., Yang, Annie S. P., van Crevel, Reinout, Aaby, Peter, de Mast, Quirijn, van der Ven, André J. A. M., Stabell Benn, Christine, Netea, Mihai G., and Sauerwein, Robert W.
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- 2019
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4. Opposing Effects of Interleukin-36γ and Interleukin-38 on Trained Immunity
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Teufel, Lisa U., primary, Netea, Mihai G., additional, van de Veerdonk, Frank L., additional, Dinarello, Charles A., additional, Joosten, Leo A. B., additional, and Arts, Rob J. W., additional
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- 2023
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5. Circulating interleukin-38 concentrations in healthy adults
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Teufel, Lisa U., primary, de Graaf, Dennis M., additional, Netea, Mihai G., additional, Dinarello, Charles A., additional, Joosten, Leo A. B., additional, and Arts, Rob J. W., additional
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- 2022
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6. Exploratory analysis of interleukin‐38 in hospitalized COVID‐19 patients.
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de Graaf, Dennis M., Teufel, Lisa U., de Nooijer, Aline H., van Gammeren, Adriaan J., Ermens, Antonius A. M., Gaál, Ildikó O., Crișan, Tania O., van de Veerdonk, Frank L., Netea, Mihai G., Dinarello, Charles A., Joosten, Leo A. B., and Arts, Rob J. W.
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COVID-19 ,HOSPITAL patients ,VIRUS diseases ,EXTRACELLULAR matrix proteins ,IMMUNOGLOBULIN receptors - Abstract
Introduction: A major contributor to coronavirus disease 2019 (COVID‐19) progression and severity is a dysregulated innate and adaptive immune response. Interleukin‐38 (IL−38) is an IL‐1 family member with broad anti‐inflammatory properties, but thus far little is known about its role in viral infections. Recent studies have shown inconsistent results, as one study finding an increase in circulating IL‐38 in COVID‐19 patients in comparison to healthy controls, whereas two other studies report no differences in IL‐38 concentrations. Methods: Here, we present an exploratory, retrospective cohort study of circulating IL‐38 concentrations in hospitalized COVID‐19 patients admitted to two Dutch hospitals (discovery n = 148 and validation n = 184) and age‐ and sex‐matched healthy subjects. Plasma IL‐38 concentrations were measured by enzyme‐linked immunosorbent assay, disease‐related proteins by proximity extension assay, and clinical data were retrieved from hospital records. Results: IL‐38 concentrations were stable during hospitalization and similar to those of healthy control subjects. IL‐38 was not associated with rates of intensive care unit admission or mortality. Only in men in the discovery cohort, IL‐38 concentrations were positively correlated with hospitalization duration. A positive correlation between IL‐38 and the inflammatory biomarker d‐dimer was observed in men of the validation cohort. In women of the validation cohort, IL‐38 concentrations correlated negatively with thrombocyte numbers. Furthermore, plasma IL‐38 concentrations in the validation cohort correlated positively with TNF, TNFRSF9, IL‐10Ra, neurotrophil 3, polymeric immunoglobulin receptor, CHL1, CD244, superoxide dismutase 2, and fatty acid binding protein 2, and negatively with SERPINA12 and cartilage oligomeric matrix protein. Conclusions: These data indicate that IL‐38 is not associated with disease outcomes in hospitalized COVID‐19 patients. However, moderate correlations between IL‐38 concentrations and biomarkers of disease were identified in one of two cohorts. While we demonstrate that IL‐38 concentrations are not indicative of COVID‐19 severity, its anti‐inflammatory effects may reduce COVID‐19 severity and should be experimentally investigated. [ABSTRACT FROM AUTHOR]
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- 2022
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7. induction of trained immunity in adherent human monocytes
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Domínguez-Andrés, Jorge, Arts, Rob J W, Bekkering, Siroon, Bahrar, Harsh, Blok, Bastiaan A, de Bree, L Charlotte J, Bruno, Mariolina, Bulut, Özlem, Debisarun, Priya A, Dijkstra, Helga, Cristina Dos Santos, Jéssica, Ferreira, Anaísa V, Flores-Gomez, Daniela, Groh, Laszlo A, Grondman, Inge, Helder, Leonie, Jacobs, Cor, Jacobs, Liesbeth, Jansen, Trees, Kilic, Gizem, Klück, Viola, Koeken, Valerie A C M, Lemmers, Heidi, Moorlag, Simone J C F M, Mourits, Vera P, van Puffelen, Jelmer H, Rabold, Katrin, Röring, Rutger J, Rosati, Diletta, Tercan, Helin, van Tuijl, Julia, Quintin, Jessica, van Crevel, Reinout, Riksen, Niels P, Joosten, Leo A B, Netea, Mihai G, and CiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover.
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Cell biology ,Cell isolation ,Immunology ,Cell-based assays - Abstract
A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed "trained immunity." We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using β-glucan (from Candida albicans) and Bacillus Calmette-Guérin as examples. For complete details on the use and execution of this protocol, please refer to Repnik et al. (2003) and Bekkering et al. (2016).
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- 2021
8. Altered Ex-Vivo Cytokine Responses in Children With Asymptomatic Plasmodium falciparum Infection in Burkina Faso: An Additional Argument to Treat Asymptomatic Malaria?
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Post, Annelies, primary, Kaboré, Berenger, additional, Berendsen, Mike, additional, Diallo, Salou, additional, Traore, Ousmane, additional, Arts, Rob J. W., additional, Netea, Mihai G., additional, Joosten, Leo A. B., additional, Tinto, Halidou, additional, Jacobs, Jan, additional, de Mast, Quirijn, additional, and van der Ven, André, additional
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- 2021
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9. IL-38 prevents induction of trained immunity by inhibition of mTOR signaling
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de Graaf, Dennis M, primary, Teufel, Lisa U, additional, van de Veerdonk, Frank L, additional, Joosten, Leo A B, additional, Netea, Mihai G, additional, Dinarello, Charles A, additional, and Arts, Rob J W, additional
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- 2021
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10. Controlled Human Malaria Infection Induces Long-Term Functional Changes in Monocytes
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Walk, Jona, primary, Keramati, Farid, additional, de Bree, L. Charlotte J., additional, Arts, Rob J. W., additional, Blok, Bas, additional, Netea, Mihai G., additional, Stunnenberg, Hendrik G., additional, and Sauerwein, Robert W., additional
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- 2020
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11. Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency
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Munoz, Marcia A., primary, Jurczyluk, Julie, additional, Simon, Anna, additional, Hissaria, Pravin, additional, Arts, Rob J. W., additional, Coman, David, additional, Boros, Christina, additional, Mehr, Sam, additional, and Rogers, Michael J., additional
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- 2019
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12. Frontline Science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst
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Grondman, Inge, primary, Arts, Rob J W, additional, Koch, Rebecca M, additional, Leijte, Guus P, additional, Gerretsen, Jelle, additional, Bruse, Niklas, additional, Kempkes, Rosalie W M, additional, ter Horst, Rob, additional, Kox, Matthijs, additional, Pickkers, Peter, additional, Netea, Mihai G, additional, and Gresnigt, Mark S, additional
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- 2019
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13. DNA Synthesis Is Activated in Mosquitoes and Human Monocytes During the Induction of Innate Immune Memory
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Cime-Castillo, Jorge, primary, Arts, Rob J. W., additional, Vargas-Ponce de León, Valeria, additional, Moreno-Torres, Ramon, additional, Hernández-Martínez, Salvador, additional, Recio-Totoro, Benito, additional, Claudio-Piedras, Fabiola, additional, Netea, Mihai G., additional, and Lanz-Mendoza, Humberto, additional
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- 2018
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14. IL‐38 prevents induction of trained immunity by inhibition of mTOR signaling
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Graaf, Dennis M., Teufel, Lisa U., Veerdonk, Frank L., Joosten, Leo A. B., Netea, Mihai G., Dinarello, Charles A., and Arts, Rob J. W.
- Abstract
Trained immunity is the acquisition of a hyperresponsive phenotype by innate immune cells (such as monocytes and macrophages) after an infection or vaccination, a de factononspecific memory dependent on epigenetic and metabolic reprogramming of these cells. We have recently shown that induction of trained immunity is dependent on IL‐1β. Here, we show that recombinant IL‐38, an anti‐inflammatory cytokine of the IL‐1‐family, was able to induce long‐term inhibitory changes and reduce the induction of trained immunity by β‐glucan in vivo in C57BL/6 mice and ex vivoin their bone marrow cells. IL‐38 blocked mTOR signaling and prevented the epigenetic and metabolic changes induced by β‐glucan. In healthy subjects, the IL1F10associated single nucleotide polymorphism rs58965312 correlated with higher plasma IL‐38 concentrations and reduced induction of trained immunity by β‐glucan ex vivo. These results indicate that IL‐38 induces long‐term anti‐inflammatory changes and also inhibits the induction of trained immunity. Recombinant IL‐38 could therefore potentially be used as a therapeutic intervention for diseases characterized by exacerbated trained immunity. IL‐38 inhibits the induction of innate immune memory
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- 2021
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15. Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance
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Braza, Mounia S., Braza, Mounia S., van Leent, Mandy M. T., Lameijer, Marnix, Sanchez-Gaytan, Brenda L., Arts, Rob J. W., Perez-Medina, Carlos, Conde, Patricia, Garcia, Mercedes R., Gonzalez-Perez, Maria, Brahmachary, Manisha, Fay, Francois, Kluza, Ewelina, Kossatz, Susanne, Dress, Regine J., Salem, Fadi, Rialdi, Alexander, Reiner, Thomas, Boros, Peter, Strijkers, Gustav J., Calcagno, Claudia C., Ginhoux, Florent, Marazzi, Ivan, Lutgens, Esther, Nicolaes, Gerry A. F., Weber, Christian, Swirski, Filip K., Nahrendorf, Matthias, Fisher, Edward A., Duivenvoorden, Raphael, Fayad, Zahi A., Netea, Mihai G., Mulder, Willem J. M., Ochando, Jordi, Braza, Mounia S., Braza, Mounia S., van Leent, Mandy M. T., Lameijer, Marnix, Sanchez-Gaytan, Brenda L., Arts, Rob J. W., Perez-Medina, Carlos, Conde, Patricia, Garcia, Mercedes R., Gonzalez-Perez, Maria, Brahmachary, Manisha, Fay, Francois, Kluza, Ewelina, Kossatz, Susanne, Dress, Regine J., Salem, Fadi, Rialdi, Alexander, Reiner, Thomas, Boros, Peter, Strijkers, Gustav J., Calcagno, Claudia C., Ginhoux, Florent, Marazzi, Ivan, Lutgens, Esther, Nicolaes, Gerry A. F., Weber, Christian, Swirski, Filip K., Nahrendorf, Matthias, Fisher, Edward A., Duivenvoorden, Raphael, Fayad, Zahi A., Netea, Mihai G., Mulder, Willem J. M., and Ochando, Jordi
- Abstract
Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8(+) T cell-mediated immunity and promoted tolerogenic CD4(+) regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance.
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- 2018
16. Oncogene-induced maladaptive activation of trained immunity in the pathogenesis and treatment of Erdheim-Chester disease
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Molteni, Raffaella, Biavasco, Riccardo, Stefanoni, Davide, Nemkov, Travis, Domínguez-Andrés, Jorge, Arts, Rob J., Merelli, Ivan, Mazza, Davide, Zambrano, Samuel, Panigada, Maddalena, Cantoni, Eleonora, Tengesdal, Isak W., Maksud, Philippe, Piras, Francesco, Cesana, Daniela, Cassina, Laura, Distefano, Gianfranco, Loffreda, Alessia, Gnani, Daniela, De Luca, Giacomo, Tomelleri, Alessandro, Campochiaro, Corrado, Joosten, Leo A.B., Dinarello, Charles A., Kajaste-Rudnitski, Anna, Haroche, Julien, Cardaci, Simone, Cenci, Simone, Dagna, Lorenzo, Doglioni, Claudio, Ferrarini, Marina, Ferrero, Elisabetta, Boletta, Alessandra, D'Alessandro, Angelo, Montini, Eugenio, Netea, Mihai G., and Cavalli, Giulio
- Abstract
Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.
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- 2021
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17. Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival
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McCall, Charles E., primary, Zabalawi, Manal, additional, Liu, Tiefu, additional, Martin, Ayana, additional, Long, David L., additional, Buechler, Nancy L., additional, Arts, Rob J. W., additional, Netea, Mihai, additional, Yoza, Barbara K., additional, Stacpoole, Peter W., additional, and Vachharajani, Vidula, additional
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- 2018
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18. High-Mobility Group Nucleosome-Binding Protein 1 as Endogenous Ligand Induces Innate Immune Tolerance in a TLR4-Sirtuin-1 Dependent Manner in Human Blood Peripheral Mononuclear Cells
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Arts, Rob J. W., primary, Huang, Po-Kai, additional, Yang, De, additional, Joosten, Leo A. B., additional, van der Meer, Jos W. M., additional, Oppenheim, Joost J., additional, Netea, Mihai G., additional, and Cheng, Shih-Chin, additional
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- 2018
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19. The Potential Role of Trained Immunity in Autoimmune and Autoinflammatory Disorders
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Arts, Rob J. W., primary, Joosten, Leo A. B., additional, and Netea, Mihai G., additional
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- 2018
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20. Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis
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Domínguez-Andrés, Jorge, primary, Arts, Rob J. W., additional, ter Horst, Rob, additional, Gresnigt, Mark S., additional, Smeekens, Sanne P., additional, Ratter, Jacqueline M., additional, Lachmandas, Ekta, additional, Boutens, Lily, additional, van de Veerdonk, Frank L., additional, Joosten, Leo A. B., additional, Notebaart, Richard A., additional, Ardavín, Carlos, additional, and Netea, Mihai G., additional
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- 2017
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21. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
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Cheng, Shih Chin, Scicluna, Brendon P., Arts, Rob J W, Gresnigt, Mark S., Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J., Kox, Matthijs, Manjeri, Ganesh R., Wagenaars, Jori A L, Cremer, Olaf L., Leentjens, Jenneke, van der Meer, Anne J., van de Veerdonk, Frank L., Bonten, Marc J., Schultz, Marcus J., Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, Netea, Mihai G., Cheng, Shih Chin, Scicluna, Brendon P., Arts, Rob J W, Gresnigt, Mark S., Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J., Kox, Matthijs, Manjeri, Ganesh R., Wagenaars, Jori A L, Cremer, Olaf L., Leentjens, Jenneke, van der Meer, Anne J., van de Veerdonk, Frank L., Bonten, Marc J., Schultz, Marcus J., Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, and Netea, Mihai G.
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- 2016
22. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
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Medische Staf Intensive Care, Infection & Immunity, Epi Infectieziekten, JC onderzoeksprogramma Infectieziekten, MMB, Cheng, Shih Chin, Scicluna, Brendon P., Arts, Rob J W, Gresnigt, Mark S., Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J., Kox, Matthijs, Manjeri, Ganesh R., Wagenaars, Jori A L, Cremer, Olaf L., Leentjens, Jenneke, van der Meer, Anne J., van de Veerdonk, Frank L., Bonten, Marc J., Schultz, Marcus J., Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, Netea, Mihai G., Medische Staf Intensive Care, Infection & Immunity, Epi Infectieziekten, JC onderzoeksprogramma Infectieziekten, MMB, Cheng, Shih Chin, Scicluna, Brendon P., Arts, Rob J W, Gresnigt, Mark S., Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J., Kox, Matthijs, Manjeri, Ganesh R., Wagenaars, Jori A L, Cremer, Olaf L., Leentjens, Jenneke, van der Meer, Anne J., van de Veerdonk, Frank L., Bonten, Marc J., Schultz, Marcus J., Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, and Netea, Mihai G.
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- 2016
23. mTOR- and HIF-1 alpha-mediated aerobic glycolysis as metabolic basis for trained immunity
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Cheng, Shih-Chin Quintin, Jessica Cramer, Robert A. and Shepardson, Kelly M. Saeed, Sadia Kumar, Vinod and Giamarellos-Bourboulis, Evangelos J. Martens, Joost H. A. Rao, Nagesha Appukudige Aghajanirefah, Ali Manjeri, Ganesh R. Li, Yang Ifrim, Daniela C. Arts, Rob J. W. van der Meer, Brian M. J. W. Deen, Peter M. T. Logie, Colin O'Neill, Luke A. and Willems, Peter van de Veerdonk, Frank L. van der Meer, Jos W. M. and Ng, Aylwin Joosten, Leo A. B. Wijmenga, Cisca and Stunnenberg, Hendrik G. Xavier, Ramnik J. Netea, Mihai G.
- Abstract
Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent beta-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD+) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1 alpha (hypoxia-inducible factor-1 alpha) pathway. Inhibition of Akt, mTOR, or HIF-1 alpha blocked monocyte induction of trained immunity, whereas the adenosine monophosphate-activated protein kinase activator metformin inhibited the innate immune response to fungal infection. Mice with a myeloid cell-specific defect in HIF-1 alpha were unable to mount trained immunity against bacterial sepsis. Our results indicate that induction of aerobic glycolysis through an Akt-mTOR-HIF-1 alpha pathway represents the metabolic basis of trained immunity.
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- 2014
24. Transcriptional and metabolic reprogramming induce an inflammatory phenotype in non-medullary thyroid carcinoma-induced macrophages
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Arts, Rob J. W., primary, Plantinga, Theo S., additional, Tuit, Sander, additional, Ulas, Thomas, additional, Heinhuis, Bas, additional, Tesselaar, Marika, additional, Sloot, Yvette, additional, Adema, Gosse J., additional, Joosten, Leo A. B., additional, Smit, Johannes W. A., additional, Netea, Mihai G., additional, Schultze, Joachim L., additional, and Netea-Maier, Romana T., additional
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- 2016
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25. Adaptive Characteristics of Innate Immune Responses in Macrophages
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Arts, Rob J. W., primary and Netea, Mihai G., additional
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- 2016
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26. Cellular metabolism of myeloid cells in sepsis
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Arts, Rob J W, primary, Gresnigt, Mark S, additional, Joosten, Leo A B, additional, and Netea, Mihai G, additional
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- 2016
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27. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines
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Blok, Bastiaan A, primary, Arts, Rob J W, additional, van Crevel, Reinout, additional, Benn, Christine Stabell, additional, and Netea, Mihai G, additional
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- 2015
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28. Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity
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Arts, Rob J W, primary, Blok, Bastiaan A, additional, Aaby, Peter, additional, Joosten, Leo A B, additional, de Jong, Dirk, additional, van der Meer, Jos W M, additional, Benn, Christine Stabell, additional, van Crevel, Reinout, additional, and Netea, Mihai G, additional
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- 2015
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29. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes
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Arts, Rob J W, primary, Blok, Bastiaan A, additional, van Crevel, Reinout, additional, Joosten, Leo A B, additional, Aaby, Peter, additional, Benn, Christine Stabell, additional, and Netea, Mihai G, additional
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- 2015
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30. Gamma-Irradiated Bacille Calmette-Guérin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males
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Hamers, Linda A. C., primary, Kox, Matthijs, additional, Arts, Rob J. W., additional, Blok, Bastiaan, additional, Leentjens, Jenneke, additional, Netea, Mihai G., additional, and Pickkers, Peter, additional
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- 2015
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31. TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors
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Arts, Rob J W, primary, Joosten, Leo A B, additional, van der Meer, Jos W M, additional, and Netea, Mihai G, additional
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- 2013
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32. Cellular metabolism of myeloid cells in sepsis
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Arts, Rob J. W., Gresnigt, Mark S., Joosten, Leo A. B., and Netea, Mihai G.
- Abstract
In recent years, it has become appreciated that immune cells have different metabolic profiles depending on their activation status. During sepsis, circulating leukocytes go through a hyperinflammatory state, which can be accompanied or followed by defective antimicrobial defenses (also described as immune tolerance or paralysis). In this review, the modulation of different cellular metabolic pathways during sepsis in monocytes and macrophages will be discussed. Glycolysis is studied extensively in sepsis and is up-regulated in hyperinflammatory cells, whereas in immune tolerance, it is often down-regulated. Few data are available on other metabolic pathways in immune cells from patients with sepsis. The pentose phosphate pathway is up-regulated during acute hyperinflammatory responses, whereas fatty acid ß-oxidation is increased later during sepsis and is associated with an anti-inflammatory (M2) phenotype of macrophages. Within the amino acid metabolism we will discuss the most studied metabolites. Collectively, these data argue that exploration of the immunometabolic pathways in sepsis is an important area of research, and the targeting of metabolic pathways may represent a promising novel strategy as a therapy of sepsis. Review on the changes in immunometabolic pathways during sepsis.
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- 2017
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33. An enigma: why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality.
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Benn, Christine S., Aaby, Peter, Arts, Rob J. W., Jensen, Kristoffer J., Netea, Mihai G., and Fisker, Ane B
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DIETARY supplements ,VITAMIN A deficiency ,MORTALITY ,DRUG dosage - Abstract
Background: Vitamin A deficiency (VAD) is associated with increased mortality. To prevent VAD, WHO recommends high-dose vitamin A supplementation (VAS) every 4-6 months for children aged between 6 months and 5 years of age in countries at risk of VAD. The policy is based on randomized clinical trials (RCTs) conducted in the late 1980s and early 1990s. Recent RCTs indicate that the policy may have ceased to be beneficial. In addition, RCTs attempting to extend the benefits to younger children have yielded conflicting results. Stratified analyses suggest that whereas some subgroups benefit more than expected from VAS, other subgroups may experience negative effects. Methods and Results: We reviewed the potential modifiers of the effect of VAS. The variable effect of VAS was not explained by underlying differences in VAD. Rather, the effect may depend on the sex of the child, the vaccine status and previous supplementation with vitamin A. Vitamin A is known to affect the Th1/Th2 balance and, in addition, recent evidence suggests that vitamin A may also induce epigenetic changes leading to down-regulation of the innate immune response. Thus VAS protects against VAD but has also important and long-lasting immunological effects, and the effect of providing VAS may vary depending on the state of the immune system. Conclusions: To design optimal VAS programmes which target those who benefit and avoid those harmed, more studies are needed. Work is ongoing to define whether neonatal VAS should be considered in subgroups. In the most recent RCT in older children, VAS doubled the mortality for males but halved mortality for females. Hence, we ur-gently need to re-assess the effect of VAS on older children in large-scale RCTs powered to study effect modification by sex and other potential effect modifiers, and with nested immunological studies. [ABSTRACT FROM AUTHOR]
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- 2015
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34. BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner.
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Koeken, Valerie A. C. M., de Bree, L. Charlotte J., Mourits, Vera P., Moorlag, Simone J. C. F. M., Walk, Jona, Cirovic, Branko, Arts, Rob J. W., Jaeger, Martin, Dijkstra, Helga, Lemmers, Heidi, Joosten, Leo A. B., Benn, Christine S., van Crevel, Reinout, Netea, Mihai G., Koeken, Valerie Acm, Moorlag, Simone Jcfm, Arts, Rob Jw, and Joosten, Leo Ab
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BCG vaccines , *INFLAMMATION , *IMMUNOLOGIC memory , *ALLERGIES , *BLOOD cells , *ORGANIZATIONAL research , *INFLAMMATION prevention , *HUMAN reproduction , *CYTOKINES , *IN vitro studies , *MONONUCLEAR leukocytes , *HUMAN research subjects , *PROTEOMICS , *STAPHYLOCOCCUS aureus , *MYCOBACTERIUM tuberculosis , *IMMUNITY , *INFLAMMATORY mediators , *LONGITUDINAL method , *PHARMACODYNAMICS - Abstract
BACKGROUNDInduction of innate immune memory, also termed trained immunity, by the antituberculosis vaccine bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known; while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases.METHODSWe investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis- and Staphylococcus aureus-induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity.RESULTSWhile BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in 3 smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination.CONCLUSIONThe capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications.FUNDINGNetherlands Organization for Scientific Research, European Research Council, and the Danish National Research Foundation. [ABSTRACT FROM AUTHOR]
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- 2020
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35. Mycobacterial growth inhibition is associated with trained innate immunity.
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Joosten, Simone A., van Meijgaarden, Krista E., Arend, Sandra M., Prins, Corine, Oftung, Fredrik, Korsvold, Gro Ellen, Kik, Sandra V., Arts, Rob J. W., van Crevel, Reinout, Netea, Mihai G., Ottenhoff, Tom H. M., Arts, Rob Jw, and Ottenhoff, Tom Hm
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- *
MYCOBACTERIUM tuberculosis , *T cells , *MYCOBACTERIUM , *SCURFIN (Protein) , *IMMUNE response - Abstract
The lack of defined correlates of protection hampers development of vaccines against tuberculosis (TB). In vitro mycobacterial outgrowth assays are thought to better capture the complexity of the human host/Mycobacterium tuberculosis (Mtb) interaction. Here, we used a mycobacterial growth inhibition assay (MGIA) based on peripheral blood mononuclear cells to investigate the capacity to control outgrowth of bacille Calmette-Guérin (BCG). Interestingly, strong control of BCG outgrowth was observed almost exclusively in individuals with recent exposure to Mtb, but not in (long-term) latent TB infection, and only modestly in BCG vaccinees. Mechanistically, control of mycobacterial outgrowth strongly correlated with the presence of a CD14dim monocyte population, but also required the presence of T cells. The nonclassical monocytes produced CXCL10, and CXCR3 receptor blockade inhibited the capacity to control BCG outgrowth. Expression of CXCR3 splice variants was altered in recently Mtb-exposed individuals. Cytokines previously associated with trained immunity were detected in MGIA supernatants, and CXCL9, CXCL10, and CXCL11 represent new markers of trained immunity. These data indicate that CXCR3 ligands are associated with trained immunity and are critical factors in controlling mycobacterial outgrowth. In conclusion, control of mycobacterial outgrowth early after exposure to Mtb is the result of trained immunity mediated by a CXCL10-producing nonclassical CD14dim monocyte subset. [ABSTRACT FROM AUTHOR]
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- 2018
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36. Immunometabolic pathways in BCG-induced trained immunity
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Marije Oosting, Carla Palma, Rob J.W. Arts, Fernando Rodrigues, Johanneke Kleinnijenhuis, Leo A. B. Joosten, Agostinho Carvalho, Reinout van Crevel, Ekta Lachmandas, Mihai G. Netea, Giuseppe Matarese, Ricardo Silvestre, Claudia La Rocca, Luís G. Gonçalves, Cristina Cunha, Ana Belinha, [et al], Universidade do Minho, Arts, Rob J. W, Carvalho, Agostinho, LA ROCCA, Claudia, Palma, Carla, Rodrigues, Fernando, Silvestre, Ricardo, Kleinnijenhuis, Johanneke, Lachmandas, Ekta, Gonçalves, Luís G, Belinha, Ana, Cunha, Cristina, Oosting, Marije, Joosten, Leo A. B, Matarese, Giuseppe, van Crevel, Reinout, and Netea, Mihai G.
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0301 basic medicine ,immunometabolism ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Chromatin remodeling ,Epigenesis, Genetic ,glycolysi ,Mice ,03 medical and health sciences ,trained immunity ,0302 clinical medicine ,Immunity ,Animals ,Humans ,Tuberculosis ,BCG ,Epigenetics ,Innate immune system ,Science & Technology ,epigenetics ,glycolysis ,Chromatin Assembly and Disassembly ,Immunity, Innate ,3. Good health ,Histone Code ,Vaccination ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,030104 developmental biology ,Histone ,monocyte ,Immunology ,BCG Vaccine ,biology.protein ,bacteria ,H3K4me3 ,Tuberculosis vaccines ,monocytes ,Immunologic Memory ,epigenetic ,030215 immunology - Abstract
Summary The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation., Graphical Abstract, Highlights • Cellular metabolism undergoes major shifts in BCG-trained monocytes • The Akt-mTOR signaling pathway is essential for these shifts in metabolism • Induction of glucose and glutamine metabolism are crucial in trained immunity • The metabolic changes are the result of rewiring of chromatin modifications, Arts et al. found that glycolysis and glutamine metabolism, regulated by the Akt-mTOR pathway, are central mediators for the induction of trained immunity by BCG in monocytes. They show that metabolic changes are dependent on changes in histone modifications, which are influenced by metabolic changes.
- Published
- 2016
37. Anticytokine Autoantibodies in Infectious Diseases: A Practical Overview.
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Arts RJW, Janssen NAF, and van de Veerdonk FL
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- Humans, Autoimmunity, Cytokines, Immunomodulation, Autoantibodies, Communicable Diseases
- Abstract
Anticytokine autoantibodies (ACAAs) are a fascinating group of antibodies that have gained more and more attention in the field of autoimmunity and secondary immunodeficiencies over the years. Some of these antibodies are characterized by their ability to target and neutralize specific cytokines. ACAAs can play a role in the susceptibility to several infectious diseases, and their infectious manifestations depending on which specific immunological pathway is affected. In this review, we will give an outline per infection in which ACAAs might play a role and whether additional immunomodulatory treatment next to antimicrobial treatment can be considered. Finally, we describe the areas for future research on ACAAs.
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- 2023
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38. A difficult to treat Leishmania infantum relapse after allogeneic stem cell transplantation.
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Arts RJW, Ector GICG, Bosch-Nicolau P, Molina I, McCall MBB, van der Velden WJFM, van Laarhoven A, de Mast Q, and van Dorp S
- Abstract
Here we describe a complicated case of a relapsed Leishmania infantum infection after an allogeneic stem cell transplantation (allo-SCT) for primary myelofibrosis. Three years earlier the patient had been diagnosed with a hemophagocytic lymphohistiocytosis secondary to a visceral Leishmania infantum infection, for which he was effectively treated with a cumulative dose of 40 mg/kg liposomal amphotericin B. During the first disease episode he was also diagnosed with primary myelofibrosis for which he received medical follow-up. One year later ruxolitinib was started due to progressive disease. No Leishmania relapse occurred. Nevertheless, the marrow fibrosis progressed, and an allo-SCT was performed. Two months after allo-SCT prolonged fever and a persistent pancytopenia occurred, which was due to a relapse of visceral Leishmaniasis. The infection was refractory to a prolonged treatment with liposomal amphotericin B with a cumulative dose up to 100 mg/kg. Salvage treatment with miltefosine led to reduction of fever within a few days and was followed by a slow recovery of pancytopenia over the following months. The Leishmania parasite load by PCR started to decline and after 3.5 months no Leishmania DNA could be detected anymore and follow-up until ten months afterwards did not show a relapse., Competing Interests: None., (© 2023 The Authors.)
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- 2023
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39. Effect of exogenous IL-37 on immune cells from a patient carrying a potential IL37 loss-of-function variant: A case study.
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Teufel LU, van der Made CI, Klück V, Simons A, Hoischen A, Vernimmen V, Joosten LAB, and Arts RJW
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- Humans, Cytokines genetics, Inflammation, Gene Expression, Interleukin-1 metabolism, Interleukin-17 genetics
- Abstract
Introduction: Chronic inflammatory or autoimmune diseases are commonly treated with immunosuppressive medication such as NSAIDs, corticosteroids, or antibodies against specific cytokines (TNF, IL-1 IL-17, IL-23, etc.) or signalling cascades (e.g. JAK-STAT inhibitors). Using sequencing data to locate genetic mutations in relevant genes allows the identification of alternative targets in a patient-tailored therapy setting. Interleukin (IL)-37 is an anti-inflammatory cytokine with broad effects on innate and adaptive immune cell function. Dysfunctional IL-37 expression or signalling is linked to various autoinflammatory disorders. The administration of recombinant IL-37 to hyperinflammatory patients that are non-responsive to standard treatment bears the potential to alleviate symptoms., Methods: In this case study, the (hyper)responsiveness of immune cell subsets was investigated in a single patient with a seronegative autoimmune disorder who carries a heterozygous stop-gain variant in IL37 (IL37 Chr2(GRCh37):g.113670640G > A NM_014439.3:c.51G > A p.(Trp17*)). As the patient has been non-responsive to blockage of TNF or IL-1 by Etanercept or Anakinra, respectively, additional in-vitro experiments were set out to elucidate whether treatment with recombinant IL-37 could normalise observed immune cell functions., Findings: Characterisation of immune cell function showed no elevated overall production of acute-phase pro-inflammatory cytokines by patient PBMCs and neutrophils at baseline or upon stimulation. T-cell responses were elevated, as was the metabolic activity and IL-1Ra production of PBMCs at baseline. The identified stop-gain variant in IL37 does not result in the absence of the protein in circulation. In line with this, treatment with recombinant IL-37 did overall not dampen immune responses with the exception of the complete suppression of IL-17., Conclusion: The heterozygous stop-gain variant in IL37 (IL37 NM_014439.3:c.51G > A p.(Trp17*)) is not of functional relevance as we observed no clear pro-inflammatory phenotype in immune cells of a patient carrying this variant., 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 © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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40. IL-1 family cytokines as drivers and inhibitors of trained immunity.
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Teufel LU, Arts RJW, Netea MG, Dinarello CA, and Joosten LAB
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- Cells, Cultured, Interleukin-1, Cytokines, Immunity, Innate
- Abstract
Trained immunity is the long-term memory of innate immune cells, characterised by increased pro-inflammatory responses towards homo- and heterologous secondary stimuli. Interleukin (IL)-1 signalling plays an essential role in the induction of trained immunity, also called innate immune memory. As such, certain anti-inflammatory members of the IL-1 family of cytokines (IL-1F) which interfere with the inflammatory process have the potential to regulate the induction of a trained phenotype. The aim of this review is to provide an update on the role of IL-1F members in the context of trained immunity, emphasising the role of anti-inflammatory cytokines from the IL-1F to inhibit the induction of trained immunity, and touching upon their potential as therapeutics in IL-1-driven inflammatory disorders., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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41. The anti-inflammatory cytokine interleukin-37 is an inhibitor of trained immunity.
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Cavalli G, Tengesdal IW, Gresnigt M, Nemkov T, Arts RJW, Domínguez-Andrés J, Molteni R, Stefanoni D, Cantoni E, Cassina L, Giugliano S, Schraa K, Mills TS, Pietras EM, Eisenmensser EZ, Dagna L, Boletta A, D'Alessandro A, Joosten LAB, Netea MG, and Dinarello CA
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- Animals, Candidiasis genetics, Candidiasis immunology, Candidiasis microbiology, Epigenesis, Genetic drug effects, Glycolysis drug effects, Glycolysis genetics, Host-Pathogen Interactions drug effects, Host-Pathogen Interactions immunology, Humans, Male, Mice, Inbred C57BL, Neutrophils drug effects, Neutrophils metabolism, Mice, Anti-Inflammatory Agents pharmacology, Immunity, Innate drug effects, Interleukin-1 pharmacology
- Abstract
Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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42. In vitro induction of trained immunity in adherent human monocytes.
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Domínguez-Andrés J, Arts RJW, Bekkering S, Bahrar H, Blok BA, de Bree LCJ, Bruno M, Bulut Ö, Debisarun PA, Dijkstra H, Cristina Dos Santos J, Ferreira AV, Flores-Gomez D, Groh LA, Grondman I, Helder L, Jacobs C, Jacobs L, Jansen T, Kilic G, Klück V, Koeken VACM, Lemmers H, Moorlag SJCFM, Mourits VP, van Puffelen JH, Rabold K, Röring RJ, Rosati D, Tercan H, van Tuijl J, Quintin J, van Crevel R, Riksen NP, Joosten LAB, and Netea MG
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- Cellular Reprogramming physiology, Cytokines immunology, Humans, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear physiology, Monocytes physiology, Mycobacterium bovis physiology, beta-Glucans pharmacology, Cellular Reprogramming Techniques methods, Immunity, Innate immunology
- Abstract
A growing number of studies show that innate immune cells can undergo functional reprogramming, facilitating a faster and enhanced response to heterologous secondary stimuli. This concept has been termed "trained immunity." We outline here a protocol to recapitulate this in vitro using adherent monocytes from consecutive isolation of peripheral blood mononuclear cells. The induction of trained immunity and the associated functional reprogramming of monocytes is described in detail using β-glucan (from Candida albicans ) and Bacillus Calmette-Guérin as examples. For complete details on the use and execution of this protocol, please refer to Repnik et al. (2003) and Bekkering et al. (2016)., Competing Interests: The authors declare no competing interests, (© 2021 The Author(s).)
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- 2021
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43. The role of Toll-like receptor 10 in modulation of trained immunity.
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Mourits VP, Arts RJW, Novakovic B, Matzaraki V, de Bree LCJ, Koeken VACM, Moorlag SJCFM, van Puffelen JH, Groh L, van der Heijden CDCC, Keating ST, Netea MG, Oosting M, and Joosten LAB
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- Adolescent, Adult, Aged, Cells, Cultured, Female, Humans, Interleukin 1 Receptor Antagonist Protein metabolism, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Male, Middle Aged, Mutation, Missense, Randomized Controlled Trials as Topic, Signal Transduction, Toll-Like Receptor 10 genetics, Toll-Like Receptor 10 immunology, Toll-Like Receptor 10 metabolism, Up-Regulation, Young Adult, BCG Vaccine administration & dosage, Immunity, Innate drug effects, Leukocytes, Mononuclear drug effects, Toll-Like Receptor 10 agonists, Vaccination
- Abstract
Toll-like receptor 10 (TLR10) is the only member of the human Toll-like receptor family with an inhibitory function on the induction of innate immune responses and inflammation. However, its role in the modulation of trained immunity (innate immune memory) is unknown. In the present study, we assessed whether TLR10 modulates the induction of trained immunity induced by β-glucan or bacillus Calmette-Guérin (BCG). Interleukin 10 receptor antagonist production was increased upon activation of TLR10 ex vivo after BCG vaccination, and TLR10 protein expression on monocytes was increased after BCG vaccination, whereas anti-TLR10 antibodies did not significantly modulate β-glucan or BCG-induced trained immunity in vitro. A known immunomodulatory TLR10 missense single-nucleotide polymorphism (rs11096957) influenced trained immunity responses by β-glucan or BCG in vitro. However, the in vivo induction of trained immunity by BCG vaccination was not influenced by TLR10 polymorphisms. In conclusion, TLR10 has a limited, non-essential impact on the induction of trained immunity in humans., (© 2019 The Authors. Immunology published by John Wiley & Sons Ltd.)
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- 2020
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44. The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity.
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Domínguez-Andrés J, Novakovic B, Li Y, Scicluna BP, Gresnigt MS, Arts RJW, Oosting M, Moorlag SJCFM, Groh LA, Zwaag J, Koch RM, Ter Horst R, Joosten LAB, Wijmenga C, Michelucci A, van der Poll T, Kox M, Pickkers P, Kumar V, Stunnenberg H, and Netea MG
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- Adolescent, Adult, Animals, Endotoxemia chemically induced, Healthy Volunteers, Humans, Immune Tolerance, Immunity, Innate, Lipopolysaccharides, Male, Mice, Monocytes cytology, RAW 264.7 Cells, Young Adult, Carboxy-Lyases metabolism, Endotoxemia immunology, Escherichia coli Infections immunology, Monocytes immunology, Succinate Dehydrogenase metabolism, Succinates metabolism
- Abstract
Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immunity by β-glucan counteracted tolerance induced in a model of human endotoxemia by inhibiting the expression of immune-responsive gene 1 (IRG1), the enzyme that controls itaconate synthesis. β-Glucan also increased the expression of succinate dehydrogenase (SDH), contributing to the integrity of the TCA cycle and leading to an enhanced innate immune response after secondary stimulation. The role of itaconate was further validated by IRG1 and SDH polymorphisms that modulate induction of tolerance and trained immunity in human monocytes. These data demonstrate the importance of the IRG1-itaconate-SDH axis in the development of immune tolerance and training and highlight the potential of β-glucan-induced trained immunity to revert immunoparalysis., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2019
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45. Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.
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Braza MS, van Leent MMT, Lameijer M, Sanchez-Gaytan BL, Arts RJW, Pérez-Medina C, Conde P, Garcia MR, Gonzalez-Perez M, Brahmachary M, Fay F, Kluza E, Kossatz S, Dress RJ, Salem F, Rialdi A, Reiner T, Boros P, Strijkers GJ, Calcagno CC, Ginhoux F, Marazzi I, Lutgens E, Nicolaes GAF, Weber C, Swirski FK, Nahrendorf M, Fisher EA, Duivenvoorden R, Fayad ZA, Netea MG, Mulder WJM, and Ochando J
- Subjects
- Allografts, Animals, Biomarkers, HMGB1 Protein genetics, Immune Tolerance, Immunity, Innate, Immunologic Memory, Macrophages immunology, Macrophages metabolism, Mice, TOR Serine-Threonine Kinases metabolism, Vimentin genetics, Graft Survival immunology, Immunosuppression Therapy, Inflammation immunology, Myeloid Cells immunology, Myeloid Cells metabolism, Organ Transplantation
- Abstract
Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8
+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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46. Metabolic Induction of Trained Immunity through the Mevalonate Pathway.
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Bekkering S, Arts RJW, Novakovic B, Kourtzelis I, van der Heijden CDCC, Li Y, Popa CD, Ter Horst R, van Tuijl J, Netea-Maier RT, van de Veerdonk FL, Chavakis T, Joosten LAB, van der Meer JWM, Stunnenberg H, Riksen NP, and Netea MG
- Subjects
- Animals, Cells, Cultured, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Male, Mice, Mice, Inbred C57BL, Monocytes drug effects, Receptor, IGF Type 1 metabolism, Immunity, Innate, Immunologic Memory, Mevalonate Kinase Deficiency immunology, Mevalonic Acid metabolism, Monocytes immunology
- Abstract
Innate immune cells can develop long-term memory after stimulation by microbial products during infections or vaccinations. Here, we report that metabolic signals can induce trained immunity. Pharmacological and genetic experiments reveal that activation of the cholesterol synthesis pathway, but not the synthesis of cholesterol itself, is essential for training of myeloid cells. Rather, the metabolite mevalonate is the mediator of training via activation of IGF1-R and mTOR and subsequent histone modifications in inflammatory pathways. Statins, which block mevalonate generation, prevent trained immunity induction. Furthermore, monocytes of patients with hyper immunoglobulin D syndrome (HIDS), who are mevalonate kinase deficient and accumulate mevalonate, have a constitutive trained immunity phenotype at both immunological and epigenetic levels, which could explain the attacks of sterile inflammation that these patients experience. Unraveling the role of mevalonate in trained immunity contributes to our understanding of the pathophysiology of HIDS and identifies novel therapeutic targets for clinical conditions with excessive activation of trained immunity., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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47. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity.
- Author
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Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang SY, Oosting M, Kumar V, Xavier RJ, Wijmenga C, Joosten LAB, Reusken CBEM, Benn CS, Aaby P, Koopmans MP, Stunnenberg HG, van Crevel R, and Netea MG
- Subjects
- Adult, Cellular Reprogramming genetics, Epigenesis, Genetic genetics, Humans, Interferon-gamma blood, Interleukin-1beta genetics, Interleukin-1beta immunology, Male, Polymorphism, Single Nucleotide genetics, Vaccination, Viremia prevention & control, Virus Diseases immunology, Yellow Fever immunology, Yellow Fever virology, Young Adult, BCG Vaccine immunology, Interleukin-1beta blood, Monocytes immunology, Mycobacterium bovis immunology, Virus Diseases prevention & control, Yellow Fever prevention & control, Yellow fever virus immunology
- Abstract
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response. The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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48. Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity.
- Author
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Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, Rodrigues F, Silvestre R, Cheng SC, Wang SY, Habibi E, Gonçalves LG, Mesquita I, Cunha C, van Laarhoven A, van de Veerdonk FL, Williams DL, van der Meer JW, Logie C, O'Neill LA, Dinarello CA, Riksen NP, van Crevel R, Clish C, Notebaart RA, Joosten LA, Stunnenberg HG, Xavier RJ, and Netea MG
- Subjects
- Cholesterol metabolism, Glucose metabolism, Glycolysis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Immune Tolerance, Macrophages metabolism, Models, Biological, Pentose Phosphate Pathway genetics, Proteolysis, Epigenesis, Genetic, Fumarates metabolism, Glutamine metabolism, Immunity, Innate genetics
- Abstract
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., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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49. Immunometabolic Pathways in BCG-Induced Trained Immunity.
- Author
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Arts RJW, Carvalho A, La Rocca C, Palma C, Rodrigues F, Silvestre R, Kleinnijenhuis J, Lachmandas E, Gonçalves LG, Belinha A, Cunha C, Oosting M, Joosten LAB, Matarese G, van Crevel R, and Netea MG
- Subjects
- Animals, Chromatin Assembly and Disassembly genetics, Chromatin Assembly and Disassembly immunology, Epigenesis, Genetic immunology, Glycolysis immunology, Histone Code genetics, Humans, Mice, Monocytes immunology, Tuberculosis microbiology, Tuberculosis prevention & control, BCG Vaccine immunology, Immunity, Innate, Immunologic Memory genetics, Tuberculosis immunology
- Abstract
The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
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50. β-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance.
- Author
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Novakovic B, Habibi E, Wang SY, Arts RJW, Davar R, Megchelenbrink W, Kim B, Kuznetsova T, Kox M, Zwaag J, Matarese F, van Heeringen SJ, Janssen-Megens EM, Sharifi N, Wang C, Keramati F, Schoonenberg V, Flicek P, Clarke L, Pickkers P, Heath S, Gut I, Netea MG, Martens JHA, Logie C, and Stunnenberg HG
- Subjects
- Cell Differentiation, DNA Methylation, Epigenomics, Gene Regulatory Networks, Histone Code, Humans, Immunity, Innate, Immunologic Memory, Macrophages cytology, Monocytes cytology, Sepsis genetics, Immune Tolerance, Lipopolysaccharides immunology, Macrophages immunology, Monocytes immunology, Sepsis immunology, Transcription, Genetic, beta-Glucans immunology
- Abstract
Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as lipopolysaccharide (LPS). We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time-dependent manner. Mechanistically, LPS-treated monocytes fail to accumulate active histone marks at promoter and enhancers of genes in the lipid metabolism and phagocytic pathways. Transcriptional inactivity in response to a second LPS exposure in tolerized macrophages is accompanied by failure to deposit active histone marks at promoters of tolerized genes. In contrast, β-glucan partially reverses the LPS-induced tolerance in vitro. Importantly, ex vivo β-glucan treatment of monocytes from volunteers with experimental endotoxemia re-instates their capacity for cytokine production. Tolerance is reversed at the level of distal element histone modification and transcriptional reactivation of otherwise unresponsive genes. VIDEO ABSTRACT., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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