Abstract
There is a growing appreciation that metabolic processes and individual metabolites can shape the function of immune cells and thereby play important roles in the outcome of immune responses. In this respect, the use of MS- and NMR spectroscopy-based platforms to characterize and quantify metabolites in biological samples has recently yielded important novel insights into how our immune system functions and has contributed to the identification of biomarkers for immune-mediated diseases. Here, these recent immunological studies in which metabolomics has been used and made significant contributions to these fields will be discussed. In particular the role of metabolomics to the rapidly advancing field of cellular immunometabolism will be highlighted as well as the future prospects of such metabolomic tools in immunology.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Vander Heiden MG (2011) Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov 10(9):671–684. https://doi.org/10.1038/nrd3504
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. https://doi.org/10.1126/science.1160809
O’Neill LA, Kishton RJ, Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16(9):553–565. https://doi.org/10.1038/nri.2016.70
O’Sullivan D, Pearce EL (2015) Targeting T cell metabolism for therapy. Trends Immunol 36(2):71–80. https://doi.org/10.1016/j.it.2014.12.004
Pelgrom LR, van der Ham AJ, Everts B (2016) Analysis of TLR-induced metabolic changes in dendritic cells using the seahorse XF(e)96 extracellular flux analyzer. Methods Mol Biol 1390:273–285. https://doi.org/10.1007/978-1-4939-3335-8_17
Van den Bossche J, O’Neill LA, Menon D (2017) Macrophage immunometabolism: where are we (Going)? Trends Immunol. https://doi.org/10.1016/j.it.2017.03.001
Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O’Neill LA (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496(7444):238–242. https://doi.org/10.1038/nature11986
Mills EL, Kelly B, Logan A, Costa AS, Varma M, Bryant CE, Tourlomousis P, Dabritz JH, Gottlieb E, Latorre I, Corr SC, McManus G, Ryan D, Jacobs HT, Szibor M, Xavier RJ, Braun T, Frezza C, Murphy MP, O’Neill LA (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167(2):457–470.e413. https://doi.org/10.1016/j.cell.2016.08.064
Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE, Loginicheva E, Cervantes-Barragan L, Ma X, Huang SC, Griss T, Weinheimer CJ, Khader S, Randolph GJ, Pearce EJ, Jones RG, Diwan A, Diamond MS, Artyomov MN (2016) Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 24(1):158–166. https://doi.org/10.1016/j.cmet.2016.06.004
Dennis EA, Deems RA, Harkewicz R, Quehenberger O, Brown HA, Milne SB, Myers DS, Glass CK, Hardiman G, Reichart D, Merrill AH Jr, Sullards MC, Wang E, Murphy RC, Raetz CR, Garrett TA, Guan Z, Ryan AC, Russell DW, McDonald JG, Thompson BM, Shaw WA, Sud M, Zhao Y, Gupta S, Maurya MR, Fahy E, Subramaniam S (2010) A mouse macrophage lipidome. J Biol Chem 285(51):39976–39985. https://doi.org/10.1074/jbc.M110.182915
Lee JW, Mok HJ, Lee DY, Park SC, Kim GS, Lee SE, Lee YS, Kim KP, Kim HD (2017) UPLC-QqQ/MS-based lipidomics approach to characterize lipid alterations in inflammatory macrophages. J Proteome Res 16(4):1460–1469. https://doi.org/10.1021/acs.jproteome.6b00848
Huang SC, Everts B, Ivanova Y, O’Sullivan D, Nascimento M, Smith AM, Beatty W, Love-Gregory L, Lam WY, O’Neill CM, Yan C, Du H, Abumrad NA, Urban JF Jr, Artyomov MN, Pearce EL, Pearce EJ (2014) Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15(9):846–855. https://doi.org/10.1038/ni.2956
Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, Pearce EJ, Driggers EM, Artyomov MN (2015) Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42(3):419–430. https://doi.org/10.1016/j.immuni.2015.02.005
van der Windt GJ, Pearce EL (2012) Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 249(1):27–42. https://doi.org/10.1111/j.1600-065X.2012.01150.x
Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35(6):871–882. https://doi.org/10.1016/j.immuni.2011.09.021
Verbist KC, Guy CS, Milasta S, Liedmann S, Kaminski MM, Wang R, Green DR (2016) Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532(7599):389–393. https://doi.org/10.1038/nature17442
Swamy M, Pathak S, Grzes KM, Damerow S, Sinclair LV, van Aalten DM, Cantrell DA (2016) Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat Immunol 17(6):712–720. https://doi.org/10.1038/ni.3439
O’Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD, Qiu J, Smith AM, Lam WY, DiPlato LM, Hsu FF, Birnbaum MJ, Pearce EJ, Pearce EL (2014) Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41(1):75–88. https://doi.org/10.1016/j.immuni.2014.06.005
Xu X, Araki K, Li S, Han JH, Ye L, Tan WG, Konieczny BT, Bruinsma MW, Martinez J, Pearce EL, Green DR, Jones DP, Virgin HW, Ahmed R (2014) Autophagy is essential for effector CD8(+) T cell survival and memory formation. Nat Immunol 15(12):1152–1161. https://doi.org/10.1038/ni.3025
Angela M, Endo Y, Asou HK, Yamamoto T, Tumes DJ, Tokuyama H, Yokote K, Nakayama T (2016) Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARgamma directs early activation of T cells. Nat Commun 7:13683. https://doi.org/10.1038/ncomms13683
Zeng H, Cohen S, Guy C, Shrestha S, Neale G, Brown SA, Cloer C, Kishton RJ, Gao X, Youngblood B, Do M, Li MO, Locasale JW, Rathmell JC, Chi H (2016) mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45(3):540–554. https://doi.org/10.1016/j.immuni.2016.08.017
Gerriets VA, Rathmell JC (2012) Metabolic pathways in T cell fate and function. Trends Immunol 33(4):168–173. https://doi.org/10.1016/j.it.2012.01.010
Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, Warmoes MO, de Cubas AA, MacIver NJ, Locasale JW, Turka LA, Wells AD, Rathmell JC (2016) Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol 17(12):1459–1466. https://doi.org/10.1038/ni.3577
Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, Kogadeeva M, Picotti P, Meissner F, Mann M, Zamboni N, Sallusto F, Lanzavecchia A (2016) L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167(3):829–842.e813. https://doi.org/10.1016/j.cell.2016.09.031
Monticelli LA, Buck MD, Flamar AL, Saenz SA, Tait Wojno ED, Yudanin NA, Osborne LC, Hepworth MR, Tran SV, Rodewald HR, Shah H, Cross JR, Diamond JM, Cantu E, Christie JD, Pearce EL, Artis D (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17(6):656–665. https://doi.org/10.1038/ni.3421
Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, Redmann V, Freitas TC, Blagih J, van der Windt GJ, Artyomov MN, Jones RG, Pearce EL, Pearce EJ (2014) TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat Immunol 15(4):323–332. https://doi.org/10.1038/ni.2833
Lachmandas E, Boutens L, Ratter JM, Hijmans A, Hooiveld GJ, Joosten LA, Rodenburg RJ, Fransen JA, Houtkooper RH, van Crevel R, Netea MG, Stienstra R (2016) Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes. Nat Microbiol 2:16246. https://doi.org/10.1038/nmicrobiol.2016.246
Buescher JM, Antoniewicz MR, Boros LG, Burgess SC, Brunengraber H, Clish CB, DeBerardinis RJ, Feron O, Frezza C, Ghesquiere B, Gottlieb E, Hiller K, Jones RG, Kamphorst JJ, Kibbey RG, Kimmelman AC, Locasale JW, Lunt SY, Maddocks OD, Malloy C, Metallo CM, Meuillet EJ, Munger J, Noh K, Rabinowitz JD, Ralser M, Sauer U, Stephanopoulos G, St-Pierre J, Tennant DA, Wittmann C, Vander Heiden MG, Vazquez A, Vousden K, Young JD, Zamboni N, Fendt SM (2015) A roadmap for interpreting (13)C metabolite labeling patterns from cells. Curr Opin Biotechnol 34:189–201. https://doi.org/10.1016/j.copbio.2015.02.003
Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, Bosca L (2010) Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol 185(1):605–614. https://doi.org/10.4049/jimmunol.0901698
Balmer ML, Ma EH, Bantug GR, Grahlert J, Pfister S, Glatter T, Jauch A, Dimeloe S, Slack E, Dehio P, Krzyzaniak MA, King CG, Burgener AV, Fischer M, Develioglu L, Belle R, Recher M, Bonilla WV, Macpherson AJ, Hapfelmeier S, Jones RG, Hess C (2016) Memory CD8(+) T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44(6):1312–1324. https://doi.org/10.1016/j.immuni.2016.03.016
Ma EH, Bantug G, Griss T, Condotta S, Johnson RM, Samborska B, Mainolfi N, Suri V, Guak H, Balmer ML, Verway MJ, Raissi TC, Tsui H, Boukhaled G, Henriques da Costa S, Frezza C, Krawczyk CM, Friedman A, Manfredi M, Richer MJ, Hess C, Jones RG (2017) Serine is an essential metabolite for effector T cell expansion. Cell Metab 25(2):345–357. https://doi.org/10.1016/j.cmet.2016.12.011
Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vazquez G, Yurchenko E, Raissi TC, van der Windt GJ, Viollet B, Pearce EL, Pelletier J, Piccirillo CA, Krawczyk CM, Divangahi M, Jones RG (2015) The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42(1):41–54. https://doi.org/10.1016/j.immuni.2014.12.030
Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, Pearce EL (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162(6):1229–1241. https://doi.org/10.1016/j.cell.2015.08.016
Romero-Garcia S, Moreno-Altamirano MM, Prado-Garcia H, Sanchez-Garcia FJ (2016) Lactate contribution to the tumor microenvironment: mechanisms, effects on immune cells and therapeutic relevance. Front Immunol 7:52. https://doi.org/10.3389/fimmu.2016.00052
Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ III, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25:1282. https://doi.org/10.1016/j.cmet.2016.12.018
Klein-Wieringa IR, Andersen SN, Kwekkeboom JC, Giera M, de Lange-Brokaar BJ, van Osch GJ, Zuurmond AM, Stojanovic-Susulic V, Nelissen RG, Pijl H, Huizinga TW, Kloppenburg M, Toes RE, Ioan-Facsinay A (2013) Adipocytes modulate the phenotype of human macrophages through secreted lipids. J Immunol 191(3):1356–1363. https://doi.org/10.4049/jimmunol.1203074
Ioan-Facsinay A, Kwekkeboom JC, Westhoff S, Giera M, Rombouts Y, van Harmelen V, Huizinga TW, Deelder A, Kloppenburg M, Toes RE (2013) Adipocyte-derived lipids modulate CD4+ T-cell function. Eur J Immunol 43(6):1578–1587. https://doi.org/10.1002/eji.201243096
Gistera A, Hansson GK (2017) The immunology of atherosclerosis. Nat Rev Nephrol 13:368. https://doi.org/10.1038/nrneph.2017.51
Tam VC (2013) Lipidomic profiling of bioactive lipids by mass spectrometry during microbial infections. Semin Immunol 25(3):240–248. https://doi.org/10.1016/j.smim.2013.08.006
Husted AS, Trauelsen M, Rudenko O, Hjorth SA, Schwartz TW (2017) GPCR-mediated signaling of metabolites. Cell Metab 25(4):777–796. https://doi.org/10.1016/j.cmet.2017.03.008
Lin L, Zhang J (2017) Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol 18(1):2. https://doi.org/10.1186/s12865-016-0187-3
Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504(7480):446–450. https://doi.org/10.1038/nature12721
Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455. https://doi.org/10.1038/nature12726
Song H, Yoo Y, Hwang J, Na YC, Kim HS (2016) Faecalibacterium prausnitzii subspecies-level dysbiosis in the human gut microbiome underlying atopic dermatitis. J Allergy Clin Immunol 137(3):852–860. https://doi.org/10.1016/j.jaci.2015.08.021
Amiot A, Dona AC, Wijeyesekera A, Tournigand C, Baumgaertner I, Lebaleur Y, Sobhani I, Holmes E (2015) (1)H NMR spectroscopy of fecal extracts enables detection of advanced colorectal neoplasia. J Proteome Res 14(9):3871–3881. https://doi.org/10.1021/acs.jproteome.5b00277
Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K, Ferrante M, Verhaegen J, Rutgeerts P, Vermeire S (2014) A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 63(8):1275–1283. https://doi.org/10.1136/gutjnl-2013-304833
Guo Z, Zhang J, Wang Z, Ang KY, Huang S, Hou Q, Su X, Qiao J, Zheng Y, Wang L, Koh E, Danliang H, Xu J, Lee YK, Zhang H (2016) Intestinal microbiota distinguish gout patients from healthy humans. Sci Rep 6:20602. https://doi.org/10.1038/srep20602
Donia MS, Fischbach MA (2015) HUMAN MICROBIOTA. Small molecules from the human microbiota. Science 349(6246):1254766. https://doi.org/10.1126/science.1254766
Saric J (2010) Interactions between immunity and metabolism - contributions from the metabolic profiling of parasite-rodent models. Parasitology 137(9):1451–1466. https://doi.org/10.1017/S0031182010000697
Munshi SU, Rewari BB, Bhavesh NS, Jameel S (2013) Nuclear magnetic resonance based profiling of biofluids reveals metabolic dysregulation in HIV-infected persons and those on anti-retroviral therapy. PLoS One 8(5):e64298. https://doi.org/10.1371/journal.pone.0064298
Alonso A, Julia A, Vinaixa M, Domenech E, Fernandez-Nebro A, Canete JD, Ferrandiz C, Tornero J, Gisbert JP, Nos P, Casbas AG, Puig L, Gonzalez-Alvaro I, Pinto-Tasende JA, Blanco R, Rodriguez MA, Beltran A, Correig X, Marsal S (2016) Urine metabolome profiling of immune-mediated inflammatory diseases. BMC Med 14(1):133. https://doi.org/10.1186/s12916-016-0681-8
Zhang A, Sun H, Wang P, Han Y, Wang X (2012) Modern analytical techniques in metabolomics analysis. Analyst 137(2):293–300. https://doi.org/10.1039/c1an15605e
Sergushichev AA, Loboda AA, Jha AK, Vincent EE, Driggers EM, Jones RG, Pearce EJ, Artyomov MN (2016) GAM: a web-service for integrated transcriptional and metabolic network analysis. Nucleic Acids Res 44(W1):W194–W200. https://doi.org/10.1093/nar/gkw266
Acknowledgments
This work was in part funded by an LUMC and Marie Curie fellowship (#631585). I declare to have no competing interests.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Everts, B. (2018). Metabolomics in Immunology Research. In: Giera, M. (eds) Clinical Metabolomics. Methods in Molecular Biology, vol 1730. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7592-1_2
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7592-1_2
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-7591-4
Online ISBN: 978-1-4939-7592-1
eBook Packages: Springer Protocols