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The Doctoral Programme
“Metabolism in Immune Responses and Inflammation”
(MET-FLAM)

Projects

References:

We aim to investigate metabolic processes and ensuing metabolites as inflammatory mediators that are common denominators of inflammatory diseases. Angiari (PhD project P1) will investigate metabolic enzymes with multiple, so called ‘moonlighting functions’ [8], in particular in the nucleus of immune cells where they can regulate gene transcription by various mechanisms [8, 9]. A comprehensive time- and activation-dependent analysis will identify a panel of metabolic enzymes whose nuclear translocation capacity is modulated during immune cell activation and polarization. These proteins will then be studied in great detail using in-vitro functional assays and in in-vivo disease models available in the consortium. ‘Moonlighting’ has also been described for macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine released from T cells and macrophages, with additional tautomerase activity [27, 28]. Sturm (project P15) will elucidate the therapeutic potential of novel inhibitors of the tautomerase activity of MIF in mouse models of inflammatory lung diseases such as asthma and acute lung injury in vivo and effector functions of human peripheral blood leukocytes in vitro. Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease associated with considerable morbidity and mortality, in which T cells play a critical role. Stradner (P14) will address the role of premature T-cell senescence and ensuing metabolic changes with regards to autophagy, mitochondrial function and the cellular energy sensor mTOR [10, 11] in systemic lupus erythematosus, using both mouse models and patient samples. Eller (P2) will analyze the metabolic effects of glucagon-like peptide 1 agonists on immune cells beyond glycemic control, especially Th1 and Th17 cells, in a mouse model of autoimmune kidney inflammation and how incretin mimetics protect the kidney [12, 13]. The skin and its appendages harbor a specific metabolic environment with several low molecular-weight compounds present that may fulfill specific physiological functions. Wolf (P17) aims to identify key skin metabolites in common chronic inflammatory skin diseases such as psoriasis or atopic dermatitis, characterize their biological roles in immune responses and determine how these are changed in the course of therapy [14, 15].

Due to its high energy demand, the heart is well known to crucially depend on a balanced metabolic state. The same applies to the vasculature, which is responsible for nutrient exchange and the removal of toxic waste products. In contrast, the lung has only recently been recognized as a metabolically highly active organ that provides, and depends on, specific metabolites for its homeostasis and immune competence. Heinemann (P4) will investigate the role of succinate, a classical Krebs cycle intermediate metabolite in, and its receptor GPR91/SUCNR1 [16] in acute lung injury and asthma models. Based on their recent observation that succinate triggers endothelial responses [17], his group hypothesizes that succinate might be involved in the regulation of lung endothelial parameters, such as barrier function and interaction with immune cells. Kargl (P5) is very interested in metabolic pathways in neutrophils such the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid oxidation [18] and their roles in neutrophil function and distinct phenotypes. Using human samples and mouse models she will dissect the interplay of metabolic rewiring, neutrophil polarization, and immunostimulatory / immunosuppressive functions in lung diseases [19, 20]. The metabolic state of structural cells in the lungs is in the focus of Kwapiszewska (P8). She has proposed that increased immune cell numbers in sclerodermic mice correlated positively with vascular and parenchymal remodeling [21, 22] and now follows up the metabolic changes induced by infiltrating inflammatory cells in lung tissue and the involved pro-inflammatory mediators leading to vasculopathy and pulmonary fibrosis in this mouse model. On a similar account, Olschewski (P10) scrutinizes the significance of elevated circulating free fatty acid in pulmonary arterial hypertension and resulting right ventricular heart failure [23, 24]. She will address the hypothesis that free fatty acids lead to endothelial dysfunction and inflammation in pulmonary arteries, thus representing a novel factor contributing to the pathophysiology of the disease, using human lungs and mouse models of pulmonary hypertension. A reverse approach is taken by Sedej (P12) in heart failure with preserved ejection fraction, where he has proposed that NAD+ supplementation has beneficial effects on a distinct population of cardiac-resident macrophages with a pro-inflammatory phenotype that promotes myocardial fibrosis [25, 26]. He will advance this concept by investigating defects in macrophage autophagy that exacerbate heart failure and identifying cardiac-specific and systemic consequences of monocyte / macrophage autophagy.

High-density lipoprotein (HDL) has numerous biological functions beyond reverse cholesterol transport [29, 30]. Marsche (P9) will determine how severe inflammation influences the metabolism of HDL and affects its composition and function, particularly its ability to neutralize lipopolysaccharide (LPS) and modulate immune and endothelial cell responses. He will test reconstituted HDL in models of acute lung inflammation to evaluate its potential therapeutic properties. Along the same line, Kratky (P7) investigates the contribution of the small intestine to HDL production, and the role of intestinal HDL in liver homeostasis and protection against LPS-, alcohol- or diet-induced hepatic inflammation [31, 32]. The metabolic pathways by which small intestinal HDL production is regulated will be clarified using mutant mouse models in various nutritional feeding states. During pregnancy, the placenta performs numerous pivotal biological functions, such as exchange of nutrients and blood gases between mother and fetus, and metabolic regulation in both directions [33]. Wadsack (P16) hypothesizes that preeclampsia, a severe and frequent gestosis, is driven by abnormal placenta-derived endothelial cell-derived extracellular vesicles (ECEVs) that cause an exacerbated inflammatory response in fetal immune cells [34]. He examines changes in the protein / lipid cargo of ECEVs and whether ECEVs trigger altered inflammatory response in fetal immune cells in preeclampsia.

Metabolomic data indicate that metabolic dysregulation is also present in multiple sclerosis (MS) patients [35]. Khalil (P6) will correlate metabolic profiles in circulating immune cells and cerebrospinal fluid, with soluble markers of inflammation [36] and disease activity, and develop novel procedures for early discrimination between disease phenotypes and stages. Immunological and clinical characteristics will also be followed up for MS-related signs of tissue damage as evidenced by magnetic resonance imaging [37]. Disability is often due to sarcopenia in the elderly [38]. Stadlbauer-Köllner (P13) has a long-standing interest in immunological and metabolic derangements in chronic liver diseases [39, 40]. In MET-FLAM she will study the impact of bile acid metabolism by the gut microbiome on intestinal permeability, systemic inflammation and muscle cell function in cirrhotic patients with and without sarcopenia. The importance of the gut microbiome for a balanced metabolic state on the one hand, and mental health on the other hand, is increasingly being recognized. The research of Farzi (P3) delineates determinants and mediators involved in the gut–brain axis and characterizes the effects of metabolic derangements and changes in the gut microbiome on mood and behavior [41]. She will test the hypothesis that Nod1 and Nod2 signaling [42] play an important role in high-fat diet-induced cognitive impairment and depression by modulating immune activation and insulin resistance in the brain. Symptoms in inflammatory bowel disease are not restricted to the intestinal tract, but can also affect brain function presenting as depression and anxiety disorders [43, 44]. To further unveil the altered gut–brain axis communication during experimental colitis Reichmann (P11) will address the role of tryptophan metabolites, produced by the microbiota, which may protect against increased gut permeability, neuroinflammation and neuroimmunological remodeling during colitis. Thus, the PhD projects that we offer within the MET-FLAM program span a broad range of research topics devoted to a better understanding of relevant human diseases, and to devising novel therapeutic approaches to them. The common denominator of the proposed dissertation topics is our focus on metabolism at the cellular, tissue and systemic level and its role in inflammatory processes, thereby ensuring high interdependency and synergism between our projects.

References:

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  2. Boukouris AE, Zervopoulos SD, Michelakis ED: Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription. Trends Biochem Sci, 2016; 41(8):712–730. doi:10.1016/j.tibs.2016.05.013
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  4. Sharabi A, Tsokos GC: T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy. Nat Rev Rheumatol, 2020; 16(2):100–112. doi:10.1038/s41584-019-0356-x
  5. Muskiet MHA, Tonneijck L, Smits MM, van Baar MJB, Kramer MHH, Hoorn EJ, Joles JA, van Raalte DH: GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol, 2017; 13:605–628. doi:10.1038/nrneph.2017.123
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  10. Atallah R, Gindlhuber J, Platzer W, Bärnthaler T, Tatzl E, Toller W, Strutz J, Rittchen S, Luschnig P, Birner-Gruenberger R, Wadsack C, Heinemann A: SUCNR1 Is Expressed in Human Placenta and Mediates Angiogenesis: Significance in Gestational Diabetes. Int J Mol Sci. 2021; 22(21):12048. doi:10.3390/ijms222112048
  11. Kumar S, Dikshit M: Metabolic Insight of Neutrophils in Health and Disease. Front Immunol, 2019; 10:2099. doi:10.3389/fimmu.2019.02099
  12. Rice CM, Davies LC, Subleski JJ, Maio N, Gonzalez-Cotto M, Andrews C, Patel NL, Palmieri EM, Weiss JM, Lee JM, Annunziata CM, Rouault TA, Durum SK, McVicar DW: Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression. Nat Commun, 2018; 9(1):5099. doi:10.1038/s41467-018-07505-2
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  16. Brittain EL, Talati M, Fessel JP, Zhu H, Penner N, Calcutt MW, West JD, Funke M, Lewis GD, Gerszten RE, Hamid R, Pugh ME, Austin ED, Newman JH, Hemnes AR: Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension. Circulation, 2016; 133(20):1936–1944. doi:10.1161/CIRCULATIONAHA.115.019351
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  18. Hulsmans M, Sager HB, Roh JD, Valero-Muñoz M, Houstis NE, Iwamoto Y, Sun Y, Wilson RM, Wojtkiewicz G, Tricot B, Osborne MT, Hung J, Vinegoni C, Naxerova K, Sosnovik DE, Zile MR, Bradshaw AD, Liao R, Tawakol A, Weissleder R, Rosenzweig A, Swirski FK, Sam F, Nahrendorf M: Cardiac macrophages promote diastolic dysfunction. J Exp Med, 2018; 215(2):423–440. doi:10.1084/jem.20171274
  19. Abdellatif M, Trummer-Herbst V, Koser F, Durand S, Adão R, Vasques-Nóvoa F, Freundt JK, Voglhuber J, Pricolo MR, Kasa M, Türk C, Aprahamian F, Herrero-Galán E, Hofer SJ, Pendl T, Rech L, Kargl J, Anto-Michel N, Ljubojevic-Holzer S, Schipke J, Brandenberger C, Auer M, Schreiber R, Koyani CN, Heinemann A, Zirlik A, Schmidt A, von Lewinski D, Scherr D, Rainer PP, von Maltzahn J, Mühlfeld C, Krüger M, Frank S, Madeo F, Eisenberg T, Prokesch A, Leite-Moreira AF, Lourenço AP, Alegre-Cebollada J, Kiechl S, Linke WA, Kroemer G, Sedej S: Nicotinamide for the treatment of heart failure with preserved ejection fraction. Sci Transl Med, 2021; 13(580):eabd7064. doi:10.1126/scitranslmed.abd7064
  20. Zhu H, Yan S, Wu J, Zhang Z, Li X, Liu Z, Ma X, Zhou L, Zhang L, Feng M, Geng Y, Zhang A, Janciauskiene S, Xu A: Serum macrophage migration inhibitory factor as a potential biomarker to evaluate therapeutic response in patients with allergic asthma: an exploratory study. J Zhejiang Univ Sci B, 2021; 22(6):512–520. doi:10.1631/jzus.B2000555
  21. Bleilevens C, Soppert J, Hoffmann A, Breuer T, Bernhagen J, Martin L, Stiehler L, Marx G, Dreher M, Stoppe C, Simon TP: Macrophage Migration Inhibitory Factor (MIF) Plasma Concentration in Critically Ill COVID-19 Patients: A Prospective Observational Study. Diagnostics (Basel), 2021; 11(2):332. doi:10.3390/diagnostics11020332
  22. Trakaki A, Marsche G: Current Understanding of the Immunomodulatory Activities of High-Density Lipoproteins. Biomedicines, 2021; 9(6):587. doi:10.3390/biomedicines9060587
  23. Trieb M, Rainer F, Stadlbauer V, Douschan P, Horvath A, Binder L, Trakaki A, Knuplez E, Scharnagl H, Stojakovic T, Heinemann Á, Mandorfer M, Paternostro R, Reiberger T, Pitarch C, Amorós A, Gerbes A, Caraceni P, Alessandria C, Moreau R, Clària J, Marsche G, Stauber RE: HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure. J Hepatol, 2020; 73(1):113–120. doi:10.1016/j.jhep.2020.01.026
  24. Han YH, Onufer EJ, Huang LH, Sprung RW, Davidson WS, Czepielewski RS, Wohltmann M, Sorci-Thomas MG, Warner BW, Randolph GJ: Enterically derived high-density lipoprotein restrains liver injury through the portal vein. Science, 2021; 373(6553):eabe6729. doi:10.1126/science.abe6729
  25. Korbelius M, Vujić N, Kuentzel KB, Obrowsky S, Rainer S, Haemmerle G, Rülicke T, Kratky D: Enterocyte-specific ATGL overexpression affects intestinal and systemic cholesterol homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids, 2022; 1867:159121. doi:10.1016/j.bbalip.2022.159121
  26. Julia T Stadler, Christian Wadsack, Gunther Marsche: Fetal High-Density Lipoproteins: Current Knowledge on Particle Metabolism, Composition and Function in Health and Disease. Biomedicines, 2021; 9(4):349. doi:10.3390/biomedicines9040349
  27. Tong M, Abrahams VM, Chamley LW: Immunological Effects of Placental Extracellular Vesicles. Immunol Cell Biol, 2018; 96(7):714–722. doi:10.1111/imcb.12049
  28. Zahoor I, Rui B, Khan J, Datta I, Giri S: An emerging potential of metabolomics in multiple sclerosis: a comprehensive overview. Cell Mol Life Sci, 2021; 78(7):3181–3203. doi:10.1007/s00018-020-03733-2
  29. Teunissen CE, Khalil M: Neurofilaments as biomarkers in multiple sclerosis. Mult Scler, 2012; 18(5):552–556. doi:10.1177/1352458512443092
  30. Schoonheim MM, Pinter D, Prouskas SE, Broeders TA, Pirpamer L, Khalil M, Ropele S, Uitdehaag BM, Barkhof F, Enzinger C, Geurts JJ: Disability in multiple sclerosis is related to thalamic connectivity and cortical network atrophy. Mult Scler, 2022; 28(1):61–70. doi:10.1177/13524585211008743
  31. Marty E, Liu Y, Samuel A, Or O, Lane J: A review of sarcopenia: Enhancing awareness of an increasingly prevalent disease. Bone, 2017; 105:276–286. doi:10.1016/j.bone.2017.09.008
  32. Traub J, Reiss L, Aliwa B, Stadlbauer V: Malnutrition in Patients with Liver Cirrhosis. Nutrients, 2021; 13(2):540. doi:10.3390/nu13020540
  33. Balazs I, Horvath A, Leber B, Feldbacher N, Sattler W, Rainer F, Fauler G, Vermeren S, Stadlbauer V: Serum bile acids in liver cirrhosis promote neutrophil dysfunction. Clin Transl Med, 2022; 12(2):e735. doi:10.1002/ctm2.735
  34. Hassan AM, Mancano G, Kashofer K, Liebisch G, Farzi A, Zenz G, Claus SP, Holzer P: Anhedonia induced by high-fat diet in mice depends on gut microbiota and leptin. Nutr Neurosci, 2020; 25(2):299–312. doi:10.1080/1028415X.2020.1751508
  35. Farzi A, Reichmann F, Meinitzer A, Mayerhofer R, Jain P, Hassan AM, Fröhlich EE, Wagner K, Painsipp E, Rinner B, Holzer P: Synergistic effects of NOD1 or NOD2 and TLR4 activation on mouse sickness behavior in relation to immune and brain activity markers. Brain Behav Immun, 2015; 44:106–120. doi:10.1016/j.bbi.2014.08.011
  36. Iyer N, Corr SC: Gut Microbial Metabolite-Mediated Regulation of the Intestinal Barrier in the Pathogenesis of Inflammatory Bowel Disease. Nutrients, 2021; 13(12):4259. doi:10.3390/nu13124259
  37. Reichmann F, Hassan A, Farzi A, Jain P, Schuligoi R, Holzer P: Dextran sulfate sodium-induced colitis alters stress-associated behaviour and neuropeptide gene expression in the amygdala-hippocampus network of mice. Sci Rep, 2015; 5:9970. doi:10.1038/srep09970

06.06.2022 MET-FLAM – Doctoral Programme “Metabolism in Immune Responses and Inflammation”