OR04-2 Aldosterone Induces Trained Immunity via Fatty Acid Synthesis

Abstract

Hyperaldosteronism is associated with an increased cardiovascular risk in humans. Animal models show that aldosterone accelerates the development of atherosclerotic plaques, and suggest that this is, at least in part, mediated by activation of innate immune cells by aldosterone (1). Human data are scarce. We recently showed that monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation, which has been termed ‘trained immunity’ (2). Therefore, we tested the hypothesis that aldosterone induces ‘trained immunity’ by investigating the functional, immunometabolic and epigenetic effects of aldosterone on human monocytes in vitro. Human monocytes were exposed to vehicle, aldosterone (10nM) or serum obtained from patients with primary hyperaldosteronism (PA) with and without addition of a mineralocorticoid receptor (MR) antagonist for 24 hours, and differentiated to macrophages. We assessed the ability of these cells to produce ROS and cytokines upon re-stimulation. Changes in immunometabolism were assessed via extracellular flux measurements with Seahorse XF technology and further explored at the genome level with RNA microarray. Chromatin immunoprecipitation was performed to assess histone modifications in aldosterone-exposed cells. In vitro exposure of human monocytes with both aldosterone and PA serum induced a trained immunity phenotype characterized by augmented IL-6 and TNF-α responses, as well as ROS production to re-stimulation, an effect that was prevented by the MR antagonist spironolactone. Aldosterone-trained cells showed no differences in glycolysis or oxidative phosphorylation compared to vehicle treated cells. Instead, RNA microarray showed upregulation of the fatty acid synthesis (FAS) pathway, which we validated with qPCR. Pharmacological inhibition of FAS abolished the induction of training by aldosterone. Moreover, the aldosterone-trained phenotype was associated with enrichment of the transcriptionally-permissive histone mark H3K4me3, at the level of the promoters of central genes in the fatty acid synthesis pathway. In conclusion, aldosterone induces a form of trained immunity which is dependent on activation of the MR and induction of fatty acid synthesis. This novel pathway of immune activation uncovers potential pharmacological targets for patients with hyperaldosteronism. To translate these findings, we have recruited 15 patients with proven primary hyperaldosteronism and 15 matched patients with essential hypertension and comprehensively assessed systemic inflammation and monocyte phenotype as well as vascular wall inflammation with fluorodeoxyglucose-positron emission tomography. The results of these analyses will be available at the time of ENDO 2019. (1) van der Heijden et al. Cardiovasc Res. 2018 Jun 1;114(7):944-953. (2) Netea et al. Science. 2016 Apr 22;352(6284)