Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Catecholamines Induce Trained Immunity In Monocytes In Vitro and In Vivo.

Abstract

Rationale: Exposure to high catecholamine levels is associated with inflammatory changes of myeloid cells and atherosclerosis, but the underlying mechanisms are only partly understood. Objective: To investigate whether the pro-inflammatory effects of noradrenaline and adrenaline can in part be explained by the induction of an immunological memory in innate immune cells, termed 'trained immunity'. Methods and Results: In vitro, we exposed human primary monocytes to (nor)adrenaline for 24 hours, after which cells were rested and differentiated to macrophages over 5 days. After restimulation with LPS on day 6, (nor)adrenaline-exposed cells showed increased TNF-alpha production. This coincided with an increase in glycolysis and oxidative phosphorylation measured with Seahorse technology on day 6 before restimulation. Inhibition of the beta-adrenoreceptor-cAMP signaling pathway prevented the induction of training. In vivo, we studied the functional, transcriptional, and epigenetic impact of peak-wise exposure to high catecholamine levels on monocytes isolated from pheochromocytoma/paraganglioma (PHEO) patients. In PHEO patients (n=10), the peripheral blood cell composition showed a myeloid bias and an increase of the inflammatory CD14+CD16++ intermediate monocyte subset compared to controls with essential hypertension (n=14). Ex vivo production of pro-inflammatory cytokines was higher in PHEO patients. These inflammatory changes persisted for 4 weeks after surgical removal of PHEO. Transcriptome analysis of circulating monocytes at baseline showed various differentially expressed genes in inflammatory pathways in PHEO patients; epigenetic profiling of the promoters of these genes suggestsenrichment of the transcriptionally-permissive chromatin mark H3K4me3, indicative of in vivo training. Conclusions: Catecholamines induce long-lasting pro-inflammatory changes in monocytes in vitro and in vivo, indicating trained immunity. Our data contribute to the understanding of pathways driving inflammatory changes in conditions characterized by high catecholamine levels, and propose that trained immunity underlies the increased cardiovascular event rate in PHEO patients.