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In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes University of Southern Denmark In Vitro experimental model of trained innate immunity in human primary monocytes Bekkering, S.; Blok, B. A.; Joosten, Leo A B; Riksen, N. P.; van Crevel, Reinout; Netea, Mihai G Published in: Clinical and Vaccine Immunology (Online) DOI: 10.1128/CVI.00349-16 Publication date: 2016 Document version: Final published version Document license: CC BY-NC Citation for pulished version (APA): Bekkering, S., Blok, B. A., Joosten, L. A. B., Riksen, N. P., van Crevel, R., & Netea, M. G. (2016). In Vitro experimental model of trained innate immunity in human primary monocytes. Clinical and Vaccine Immunology (Online), 23(12), 926-933. https://doi.org/10.1128/CVI.00349-16 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 01. Oct. 2021 crossmark In Vitro Experimental Model of Trained Innate Immunity in Human Primary Monocytes Siroon Bekkering,a* Bastiaan A. Blok,a,b,c Leo A. B. Joosten,a Niels P. Riksen,a Reinout van Crevel,a Mihai G. Neteaa Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlandsa; Research Center for Vitamins and Vaccines, Bandim Health Project, Downloaded from Statens Serum Institut, Copenhagen, Denmarkb; Odense Patient Data Explorative Network, University of Southern Denmark/Odense University Hospital, Copenhagen, Denmarkc Innate immune memory, or trained immunity, has recently been described to be an important property of cells of the innate im- mune system. Due to the increased interest in this important new field of immunological investigation, we sought to determine the optimal conditions for an in vitro experimental protocol of monocyte training using three of the most commonly used train- ing stimuli from the literature: ␤-glucan, the bacillus Calmette-Guérin (BCG) vaccine, and oxidized low-density lipoprotein (ox- LDL). We investigated and optimized a protocol of monocyte trained immunity induced by an initial training period with ␤-glu- http://cvi.asm.org/ can, BCG, or oxLDL, followed by washing and resting of the cells and, thereafter, restimulation with secondary bacterial stimuli. The training and resting time intervals were varied to identify the optimal setting for the long-term induction of trained immu- nity. Trained immunity was assessed in terms of the secondary cytokine response, the production of reactive oxygen species, cell morphology, and induction of glycolysis. Monocytes primed with ␤-glucan, BCG, and oxLDL showed increased pro- and anti- inflammatory cytokine responses upon restimulation with nonrelated stimuli. Also, all three stimuli induced a switch to glycoly- sis (the Warburg effect). These effects were most pronounced when the training interval was 24 h and the resting time interval was 6 days. Training with BCG and oxLDL also led to the increased production of reactive oxygen species, whereas training with ␤-glucan led to the decreased production of reactive oxygen species. We describe the optimal conditions for an in vitro experi- on May 19, 2017 by SYDDANSK UNIVERSITETSBIBLIOTEK mental model with human primary monocytes for study of the induction of trained innate immunity by microbial and metabolic stimuli. he immune response is a complex system of cellular and hu- a single dose of Candida albicans confers protection against rein- Tmoral components which have the ability to detect non-self- fection with Staphylococcus aureus. In vitro studies showed that the structures and confer protection against invading pathogens, C. albicans cell wall component ␤-glucan induces epigenetic re- playing a crucial role in the survival of multicellular organisms. modeling and functional reprogramming through a dectin-1/ The immune response has traditionally been divided into the in- Raf1-dependent pathway (6, 7). Second, bacillus Calmette- nate immune system and the adaptive immune system. Adaptive Guérin (BCG) vaccination of healthy human volunteers resulted immunity, with T and B cells as cellular effectors, develops over in the nonspecific upregulation of ex vivo cytokine production by several weeks after birth, is highly specific, and builds a specific isolated monocytes that persisted for at least 3 months after vac- immunological memory, leading to protection against reinfec- cination. This effect is dependent on NOD2 signaling, autophagy, tion. The innate immune system, on the other hand, is classically and epigenetic changes in histone methylation leading to in- thought to act rapidly in a nonspecific and identical manner every creased transcription and likely explains, at least in part, the ob- time that it encounters a pathogen, without having the ability to served nonspecific effects of BCG on overall mortality (8–10). build an immunological memory. Third, the atherogenic lipid oxidized low-density lipoprotein (ox- Recently, the concept that innate immunity is nonspecific and LDL) induces long-term proatherogenic changes in monocytes in completely lacks immunological memory has been challenged. vitro leading to increased proatherogenic cytokine expression, in- First, pattern recognition receptors (PRRs) confer some specific- ity to innate immunity, and second, a growing body of literature shows that innate immunity can adapt its function after a first Received 5 July 2016 Returned for modification 26 July 2016 insult (1, 2). Several studies have shown that plants and inverte- Accepted 3 October 2016 brates, organisms which lack an adaptive immune system, show Accepted manuscript posted online 12 October 2016 enhanced immune responses upon reinfection (3). This phenom- Citation Bekkering S, Blok BA, Joosten LAB, Riksen NP, van Crevel R, Netea MG. enon has recently been confirmed in higher vertebrates and hu- 2016. In vitro experimental model of trained innate immunity in human primary monocytes. Clin Vaccine Immunol 23:926–933. doi:10.1128/CVI.00349-16. mans and has been named “trained immunity” or “innate im- Editor: H. F. Rosenberg, IIS/LAD/NIAID/NIH mune memory.” Trained immunity is dependent on epigenetic Address correspondence to Mihai G. Netea, [email protected]. remodeling and on rewiring of intracellular metabolic pathways, * Present address: Siroon Bekkering, Academic Medical Centre, Amsterdam, which in turn lead to a long-term proinflammatory phenotype The Netherlands. that is characterized by increased cytokine responses (4, 5). S.B. and B.A.B. contributed equally to this article. A series of recent in vitro and in vivo experiments has revealed Supplemental material for this article may be found at http://dx.doi.org/10.1128 that the phenomenon of trained immunity is induced by both /CVI.00349-16. pathogen-associated molecular patterns (PAMPs) and a number Copyright © 2016, American Society for Microbiology. All Rights Reserved. of danger-associated molecular patterns (DAMPs). First, in mice, 926 cvi.asm.org Clinical and Vaccine Immunology December 2016 Volume 23 Number 12 In Vitro Model of Trained Innate Immunity in Monocytes creased scavenger receptor expression, decreased cholesterol ef- flux transporter expression, and, ultimately, increased foam cell formation. This effect is dependent on Toll-like receptor 4 (TLR4)/TLR2 and subsequent phosphatidylinositol 3-kinase and extracellular signal-regulated kinase activation and epigenetic changes in histone methylation (e.g., H3K4me3, H3K9me3, and H3K27me3), resulting in increased transcription (11, 12). In recent years, there has been an increased interest in immu- Downloaded from nological research in the study of trained immunity, with studies assessing different organisms and diseases (13–17) Therefore, we sought to determine the optimal conditions for an in vitro exper- imental protocol of monocyte training using three of the most commonly used training stimuli from the literature: ␤-glucan, BCG vaccine, and oxLDL. MATERIALS AND METHODS http://cvi.asm.org/ Reagents. ␤-1,3-(D)-Glucan was kindly provided by David Williams (TN, USA), BCG (vaccine Statens Serum Institut) was obtained from The Netherlands Vaccine Institute. oxLDL was prepared as described before (18). Escherichia coli lipopolysaccharide (LPS; serotype O55:B5; Sigma- Aldrich, St. Louis, MO, USA) was further purified as described previously (19), and Pam3Cys was obtained from EMC Microcollections (catalog number L2000). Luminol and zymosan (from Saccharomyces cerevisiae) were purchased from Sigma-Aldrich. FIG 1 Schematic overview of trained immunity methodology. Monocytes PBMC and monocyte isolation. Buffy coats from healthy donors were were trained for2h(2hr-T),4h(4hr-T), or 24 h (24 hr-T). After the training on May 19, 2017 by SYDDANSK UNIVERSITETSBIBLIOTEK obtained after they provided written informed consent (Sanquin Blood stimulus was washed away, the cells were rested for 24 h (24 h-R), 3 days Bank, Nijmegen, The Netherlands). Isolation of peripheral blood mono- (3d-R), or 6 days (6d-R), after which the cells were restimulated with RPMI,
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