Aldosterone induces trained immunity: the role of fatty acid synthesis.

Supranormal levels of aldosterone are associated with increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. Using a primary human in vitro model, we demonstrate that aldosterone induces trained immunity via the mineralocorticoid receptor. We identify fatty acid synthesis as a crucial pathway necessary for the induction of trained immunity in monocyte-derived macrophages and demonstrate that pharmacological inhibition of this pathway blunts aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promotes enrichment of the transcriptionally-permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis and cardiovascular disease. After isolation, human monocyte-derived macrophages were stimulated (trained) with aldosterone (10nM) or vehicle (ethanol) for 24h, which was followed by a resting period of 5 days in medium. On day 6, before or after 4h of restimulation with Pam3Cys, RNA was isolated and subjected to gene expression profiling.