Team Daniel Ketelhuth

Immunometabolism in atherosclerosis

Introduction

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. Therefore, new therapeutic strategies targeting molecular pathways regulating atherosclerosis are needed.

Major research focus

Our research has 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 that carry potent anti-inflammatory and lipid-lowering activities.

In our current projects we examine basic molecular mechanisms involved in the metabolic control of inflammation. The paradigm shift of our research is to demonstrate that targeting immunometabolic processes can be used to control vascular inflammation. By increasing the understanding of the metabolic reactions controlling the immune system, our work will lead to the development of new drugs to treat and prevent atherosclerotic CVDs.

Team members

Daniel FJ Ketelhuth PhD, Associate Professor, Team Leader

Maria Forteza de los Reyes PhD, Assistant Professor

Anneli Olsson Laboratory Assistant

Selected publications

Disruption of GPR35 Signaling in Bone Marrow-Derived Cells Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice.
Baumgartner R, Casagrande FB, Mikkelsen RB, Berg M, Polyzos KA, Forteza MJ, Arora A, Schwartz TW, Hjorth SA, Ketelhuth DFJ
Metabolites 2021 Jun;11(7):411.

Evidence that a deviation in the kynurenine pathway aggravates atherosclerotic disease in humans.
Baumgartner R, Berg M, Matic L, Polyzos KP, Forteza MJ, Hjorth SA, Schwartz TW, Paulsson-Berne G, Hansson GK, Hedin U, Ketelhuth DFJ
J Intern Med 2021 01;289(1):53-68.

3-Hydroxyanthralinic acid metabolism controls the hepatic SREBP/lipoprotein axis, inhibits inflammasome activation in macrophages, and decreases atherosclerosis in Ldlr-/- mice.
Berg M, Polyzos KA, Agardh H, Baumgartner R, Forteza MJ, Kareinen I, Gisterå A, Bottcher G, Hurt-Camejo E, Hansson GK, Ketelhuth DFJ
Cardiovasc Res 2020 10;116(12):1948-1957.

The interplay between cytokines and the Kynurenine pathway in inflammation and atherosclerosis.
Baumgartner R, Forteza MJ, Ketelhuth DFJ
Cytokine 2019 10;122:154148.

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.
Ketelhuth DFJ, Lutgens E, Bäck M, Binder CJ, Van den Bossche J, Daniel C, et al
Cardiovasc. Res. 2019 Jul;115(9):1385-1392

The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall.
Ketelhuth DFJ
Cardiovasc. Res. 2019 Jul;115(9):1408-1415

Low-Density Lipoprotein-Reactive T Cells Regulate Plasma Cholesterol Levels and Development of Atherosclerosis in Humanized Hypercholesterolemic Mice.
Gisterå A, Klement ML, Polyzos KA, Mailer RKW, Duhlin A, Karlsson MCI, et al
Circulation 2018 Nov;138(22):2513-2526

Activation of the Regulatory T-Cell/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice.
Forteza MJ, Polyzos KA, Baumgartner R, Suur BE, Mussbacher M, Johansson DK, et al
Front Immunol 2018 ;9():950

Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis.
Gisterå A, Hermansson A, Strodthoff D, Klement ML, Hedin U, Fredrikson GN, et al
J. Intern. Med. 2017 04;281(4):383-397

Adaptive Response of T and B Cells in Atherosclerosis.
Ketelhuth DF, Hansson GK
Circ. Res. 2016 Feb;118(4):668-78

Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice.
Polyzos KA, Ovchinnikova O, Berg M, Baumgartner R, Agardh H, Pirault J, et al
Cardiovasc. Res. 2015 May;106(2):295-302

Apolipoprotein B100 danger-associated signal 1 (ApoBDS-1) triggers platelet activation and boosts platelet-leukocyte proinflammatory responses.
Assinger A, Wang Y, Butler LM, Hansson GK, Yan ZQ, Söderberg-Nauclér C, et al
Thromb. Haemost. 2014 Aug;112(2):332-41

The tryptophan metabolite 3-hydroxyanthranilic acid lowers plasma lipids and decreases atherosclerosis in hypercholesterolaemic mice.
Zhang L, Ovchinnikova O, Jönsson A, Lundberg AM, Berg M, Hansson GK, et al
Eur. Heart J. 2012 Aug;33(16):2025-34

Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis.
Hermansson A, Ketelhuth DF, Strodthoff D, Wurm M, Hansson EM, Nicoletti A, et al
J. Exp. Med. 2010 May;207(5):1081-93

Identification of a danger-associated peptide from apolipoprotein B100 (ApoBDS-1) that triggers innate proatherogenic responses.
Ketelhuth DF, Rios FJ, Wang Y, Liu H, Johansson ME, Fredrikson GN, et al
Circulation 2011 Nov;124(22):2433-43, 1-7