DANIEL KETELHUTH GROUP
Cardiovascular immunology and metabolism
Cardiovascular diseases (CVDs) are the leading cause of mortality and disability worldwide, imposing a significant burden on society. Coronary heart disease and cerebrovascular disease, the two most common forms of cardiovascular disease, are caused by acute complications of atherosclerosis. CVD kills over 17 million individuals every year, which accounts for one third of all global deaths.
Although population-wide management of traditional risk factors for CVDs (e.g. hyperlipidemia, high-blood pressure, glycaemia) has reduced the incidence of cardiovascular events in developed countries, substantial residual risk remains. Thus, translational therapeutic strategies targeting novel molecular pathways regulating atherosclerosis are needed.
Atherosclerosis is a chronic inflammatory disease initiated by retention and accumulation of lipids in the artery wall, especially low-density lipoprotein (LDL), leading to maladaptive responses of innate and adaptive immune cells. Notably, metabolism and activation are fully integrated in immune cells, and systemic or microenvironmental changes in metabolism have been shown to modulate their responses.
In pioneer work, we have identified several targets to modulate the unwanted immune responses in the artery wall, including components of LDL that can trigger innate and adaptive immune cells, and metabolites of the essential amino acid tryptophan, via the Kynurenine pathway. Our research indicates that metabolites are not just ‘fuels’ in their metabolic pathways, but that they can also act as signalling molecules in immune cells and influence atherosclerosis. By increasing the understanding of the immunometabolic reactions controlling immune responses in atherogenesis, our research will lead to the development of new drugs to treat and prevent atherosclerotic CVDs.
Sources of funding
Cardiovascular Program at Karolinska Institutet
Stiftelsen för Gamla Tjänarinnor
KI Stiftelsen för Ålderssjukdomar
Stiftelsen Professor Nanna Svartz Fond
Ketelhuth DF, Lutgens E, Bäck M, Binder CJ, Van den Bossche J, Daniel C, Dumitriu IE, Hoefer I, Libby P, O'Neill L, Weber C, Evans PC. Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology. Cardiovasc Res. 2019 Jul 1;115(9):1385-1392.
Ketelhuth DF. The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall. Cardiovasc Res. 2019 Jul 1;115(9):1408-1415.
Forteza MJ, Polyzos KA, Baumgartner R, Suur BE, Mussbacher M, Johansson DK, Hermansson A, Hansson GK, Ketelhuth DF. Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice. Frontiers in Immunology. 2018; 9:950. eCollection 2018.
Gisterå A, Klement ML, Polyzos KA, Mailer RKW, Duhlin A, Karlsson MCI, Ketelhuth DF, Hansson GK. Low-Density Lipoprotein-Reactive T Cells Regulate Plasma Cholesterol Levels and Development of Atherosclerosis in Humanized Hypercholesterolemic Mice. Circulation. 2018;138:2513-2526.
Mailer RKW, Gisterå A, Polyzos KA, Ketelhuth DFJ, Hansson GK. Hypercholesterolemia Induces Differentiation of Regulatory T Cells in the Liver. Circ Res. 2017 May 26;120(11):1740-1753.
Gisterå A, Hermansson A, Strodthoff D, Klement ML, Hedin U, Fredrikson GN, Nilsson J, Hansson GK, Ketelhuth DF. Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis. J Intern Med. 2017 Apr;281(4):383-397.
Ketelhuth DF, Hermansson A, Hlawaty H, Letourneur D, Yan ZQ, Bäck M. The leukotriene B4 receptor (BLT) antagonist BIIL284 decreases atherosclerosis in ApoE-/- mice. Prostaglandins Other Lipid Mediat. 2015 Sep;121(Pt A):105-9.
Polyzos KA, Ovchinnikova O, Berg M, Baumgartner R, Agardh H, Pirault J, Gisterå A, Assinger A, Laguna-Fernandez A, Bäck M, Hansson GK, Ketelhuth DF. Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice. Cardiovasc Res. 2015 May 1;106(2):295-302.
Grasset EK, Duhlin A, Agardh HE, Ovchinnikova O, Hägglöf T, Forsell MN, Paulsson-Berne G, Hansson GK, Ketelhuth DF, Karlsson MC. Sterile inflammation in the spleen during atherosclerosis provides oxidation-specific epitopes that induce a protective B-cell response. Proc Natl Acad Sci U S A. 2015 Apr 21;112(16):E2030-8.
Assinger A, Wang Y, Butler LM, Hansson GK, Yan ZQ, Söderberg-Nauclér C, Ketelhuth DF. Apolipoprotein B100 danger-associated signal 1 (ApoBDS-1) triggers platelet activation and boosts platelet-leukocyte proinflammatory responses. Thromb Haemost. 2014 Aug;112(2):332-41.
Gisterå A, Robertson AK, Andersson J, Ketelhuth DF, Ovchinnikova O, Nilsson SK, Lundberg AM, Li MO, Flavell RA, Hansson GK. Transforming growth factor-β signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway. Sci Transl Med. 2013 Jul 31;5(196):196ra100.
Lundberg AM, Ketelhuth DF, Johansson ME, Gerdes N, Liu S, Yamamoto M, Akira S, Hansson GK. Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis. Cardiovasc Res. 2013 Jul 15;99(2):364-73.
Klingenberg R, Gerdes N, Badeau RM, Gisterå A, Strodthoff D, Ketelhuth DF, Lundberg AM, Rudling M, Nilsson SK, Olivecrona G, Zoller S, Lohmann C, Lüscher TF, Jauhiainen M, Sparwasser T, Hansson GK. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest. 2013 Mar;123(3):1323-34.
Zhang L, Ovchinnikova O, Jönsson A, Lundberg AM, Berg M, Hansson GK, Ketelhuth DF. The tryptophan metabolite 3-hydroxyanthranilic acid lowers plasma lipids and decreases atherosclerosis in hypercholesterolaemic mice. Eur Heart J. 2012 Aug;33(16):2025-34.
Ketelhuth DF, Rios FJ, Wang Y, Liu H, Johansson ME, Fredrikson GN, Hedin U, Gidlund M, Nilsson J, Hansson GK, Yan ZQ. Identification of a danger-associated peptide from apolipoprotein B100 (ApoBDS-1) that triggers innate proatherogenic responses. Circulation. 2011 Nov 29;124(22):2433-43, 1-7.
Hermansson A, Johansson DK, Ketelhuth DF, Andersson J, Zhou X, Hansson GK. Immunotherapy with tolerogenic apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation. 2011 Mar 15;123(10):1083-91.
Hermansson A*, Ketelhuth DF*, Strodthoff D, Wurm M, Hansson EM, Nicoletti A, Paulsson-Berne G, Hansson GK. Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis. J Exp Med. 2010 May 10;207(5):1081-93. * These authors contributed equally to this work.
Baumgartner R, Forteza MJ, Ketelhuth DFJ. The interplay between cytokines and the Kynurenine pathway in inflammation and atherosclerosis. Cytokine. 2017 Sep 9. pii: S1043-4666(17)30259-4.
Ketelhuth DF, Hansson GK. Adaptive Response of T and B Cells in Atherosclerosis. Circ Res. 2016 Feb 19;118(4):668-78.
Gisterå A, Ketelhuth DF. Immunostaining of Lymphocytes in Mouse Atherosclerotic Plaque. Methods Mol Biol. 2015;1339:149-59.
Polyzos KA, Ketelhuth DF. The role of the kynurenine pathway of tryptophan metabolism in cardiovascular disease. An emerging field. Hamostaseologie. 2015;35(2):128-36.
Ketelhuth DF, Hansson GK. Modulation of autoimmunity and atherosclerosis - common targets and promising translational approaches against disease. Circ J. 2015;79(5):924-33.
Ketelhuth DF, Gisterå A, Johansson DK, Hansson GK. T cell-based therapies for atherosclerosis. Curr Pharm Des. 2013;19(33):5850-8.
Ketelhuth DF, Hansson GK. Cellular immunity, low-density lipoprotein and atherosclerosis: break of tolerance in the artery wall. Thromb Haemost. 2011 Nov;106(5):779-86.