Immunometabolic regulation of atherosclerosis

Ischaemic heart disease and stroke are the most common causes of death in the world, both diseases being manifestations of atherosclerotic cardiovascular disease. Atherosclerosis is a slow process initialized by the retention and accumulation of cholesterol rich lipoproteins in the innermost layer of the artery wall. Activation of an inflammatory response with the recruitment of immune cells lead to a buildup of plaques in the vessel. Both innate immune cells, most prominently macrophages, and adaptive immune cells play important roles in all stages of the development of atherosclerosis.

Metabolism is intimately linked with atherosclerosis development. Systemically increased levels of metabolites such as cholesterol and glucose are known risk factors for atherosclerosis. The metabolism in the microenvironment of the atherosclerotic plaque shape the immune response and influence disease progression. Immune cell metabolism of glucose and amino acids have been suggested as possible targets for future therapy. While modern therapies are effective at reducing known risk factors such as hyperlipidemia, considerable risk remains and few therapies for atherosclerosis target the underlying inflammatory mechanisms that drive the disease.

In Paper I the effect of indoleamine 2,3-dioxygenase (IDO) mediated tryptophan metabolism on atherosclerosis was investigated. Pharmacological inhibition of IDO with 1-methyl- tryptophan resulted in increased atherosclerotic burden in mice. Furthermore, in vitro data showed that the expression of pro-inflammatory molecules was increased on smooth muscle cells upon IDO inhibition. Treatment with the downstream tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) reversed both the in vivo and in vitro effects of IDO inhibition.

The effects of 3-HAA on lipoprotein metabolism was studied in Paper II. Activity of the transcription factor sterol response element binding protein 2 (SREBP2) was decreased when HepG2 hepatoma cells were treated with 3-HAA. Mice treated with the pharmacological inhibitor of the 3-HAA degrading enzyme 3-HAA oxygenase had less atherosclerotic plaque size and lower plasma lipids. In vitro experiments also showed 3-HAA to be a potent inhibitor of the inflammasome in macrophages.

In Paper III we showed that the metabolism of tryptophan is altered in human atherosclerotic disease. Patients with symptoms had an impaired metabolism of tryptophan to kynurenic acid, a metabolite that can induce anti-inflammatory responses, possibly via aryl hydrocarbon receptor activation. In Paper IV we demonstrate that the small molecule dichloroacetate (DCA), a known inhibitor of glycolysis, reduces atherosclerosis lesion size, plasma lipids and reprograms the immune system towards an anti-inflammatory phenotype. We also show that DCA is a potent inhibitor of inflammasome production of IL-1β.

List of scientific papers

I. Polyzos K, Ovchinnikova O, Berg M, Baumgartner R, Agardh H, Pirault J, Gisterå A, Assinger A, Laguna Fernandez A, Bäck M, Hansson GK, Ketelhuth DFJ. Inhibition of indoleamine 2,3-dioxygenase promotes vascular inflammation and increases atherosclerosis in Apoe-/- mice. Cardiovasc Res. 2015;106(2):295-302.
https://doi.org/10.1093/cvr/cvv100

II. Berg M*, Polyzos KA*, Agardh H, Baumgartner R, Forteza MJ, Kareinen I, Gisterå A, Bottcher G, Hurt-Camejo E, Hansson GK, Ketelhuth DFJ. 3-Hydroxyanthralinic acid Metabolism Controls the Hepatic Srebp/Lipoprotein axis, Inhibits Inflammasome Activation in Macrophages, and Decreases Atherosclerosis in LDLR-/- Mice. Cardiovasc Res. 2019 Oct 7;cvz258. *Equal contribution.
https://doi.org/10.1093/cvr/cvz258

III. Baumgartner R*, Berg M*, Matic L, Polyzos KP, Forteza MJ, Hjorth SA, Schwartz TW, Paulson- Berne G, Hansson GK, Hedin U, Ketelhuth DFJ. Evidence that deviation of the Kynurenine Pathway decreases kynurenic acid production and aryl hydrocarbon receptor signaling and aggravates atherosclerotic disease in humans. *Equal contribution. [Accepted]
https://doi.org/10.1111/joim.13142

IV. Forteza MJ, Berg M, Baumgartner R, Kareinen I, Beccaria Casagrande F, Hedin U, Zhang S, Vuckovic I, Dzeja PP, Polyzos KA, Trauelsen M, Schwartz TW, Dib L, Herrmann J, Matic L, Monaco C, Ketelhuth DFJ. Pyruvate dehydrogenase kinase links glycolysis with succinate/GPR91 signalling to regulate vascular inflammation and atherosclerosis. [Manuscript]