Aldosterone induces trained immunity: the role of fatty acid synthesis

Cardiovasc Res. 2020 Feb 1;116(2):317-328. doi: 10.1093/cvr/cvz137.


Aims: Supranormal levels of aldosterone are associated with an 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. In this study, we aimed to investigate whether aldosterone can induce trained immunity in primary human monocytes in vitro and explored the underlying mechanism.

Methods and results: We exposed human monocytes to aldosterone for 24 h, after which they were rested to differentiate into monocyte-derived macrophages for 5 days, and re-stimulated with toll-like receptor 2 and 4 ligands on day 6. We demonstrated that aldosterone augments pro-inflammatory cytokine production and reactive oxygen species production in monocyte-derived macrophages after re-stimulation, via the mineralocorticoid receptor. Fatty acid synthesis was identified as a crucial pathway necessary for this induction of trained immunity and pharmacological inhibition of this pathway blunted aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promoted enrichment of the transcriptionally permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway.

Conclusion: Aldosterone induces trained immunity in vitro, which is dependent on epigenetically mediated up-regulation of fatty acid synthesis. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis, and cardiovascular disease.

Keywords: Macrophage; Aldosterone; Atherosclerosis; Cardiovascular disease; Epigenetics; Fatty acid synthesis; Immunometabolism; Mineralocorticoid; Monocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / pharmacology*
  • Cells, Cultured
  • Cytokines / immunology
  • Cytokines / metabolism
  • DNA Methylation / drug effects
  • Enzyme Induction / drug effects
  • Epigenesis, Genetic / drug effects
  • Fatty Acids / biosynthesis
  • Fatty Acids / immunology*
  • Humans
  • Immunity, Innate / drug effects*
  • Immunologic Memory / drug effects*
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Monocytes / drug effects*
  • Monocytes / immunology
  • Monocytes / metabolism
  • Phenotype
  • Primary Cell Culture
  • Promoter Regions, Genetic / drug effects
  • Reactive Oxygen Species / immunology
  • Reactive Oxygen Species / metabolism
  • Receptors, Mineralocorticoid / agonists
  • Receptors, Mineralocorticoid / immunology
  • Receptors, Mineralocorticoid / metabolism
  • Signal Transduction
  • Transcription, Genetic / drug effects


  • Cytokines
  • Fatty Acids
  • Inflammation Mediators
  • NR3C2 protein, human
  • Reactive Oxygen Species
  • Receptors, Mineralocorticoid
  • Aldosterone