Charlotte D C C van der Heijden1,2, Laszlo Groh1,2, Samuel T Keating1,2,3, Charlotte Kaffa4, Marlies P Noz1,2, Simone Kersten1,2, Antonius E van Herwaarden5, Alexander Hoischen2,3, Leo A B Joosten1,2,6, Henri J L M Timmers1, Mihai G Netea1,2,7, Niels P Riksen1,2. 1. From the Department of Internal Medicine (C.D.C.C.v.d.H., L.G., S.T.K., M.P.N., S.K., A.H., L.A.B.J., H.J.L.M.T., M.G.N., N.P.R.), Radboud University Medical Center, Nijmegen, the Netherlands. 2. Radboud Institute of Molecular Life Sciences (C.D.C.C.v.d.H., L.G., S.T.K., M.P.N., S.K., A.H., L.A.B.J., M.G.N., N.P.R.), Radboud University Medical Center, Nijmegen, the Netherlands. 3. Department of Human Genetics (S.K., A.H.), Radboud University Medical Center, Nijmegen, the Netherlands. 4. Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences (C.K.), Radboud University Medical Center, Nijmegen, the Netherlands. 5. Department of Laboratory Medicine (A.E.v.H.), Radboud University Medical Center, Nijmegen, the Netherlands. 6. Department of Medical Genetics, Iµliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania (L.A.B.J.). 7. Department for Genomics and Immunoregulation, Life and Medical Sciences 12 Institute, University of Bonn, Germany (M.G.N.).
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 proinflammatory effects of noradrenaline and adrenaline can, in part, be explained by the induction of an immunologic 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 lipopolysaccharide on day 6, (nor)adrenaline-exposed cells showed increased TNF-α (tumor necrosis factor-α) production. This coincided with an increase in glycolysis and oxidative phosphorylation measured with Seahorse technology on day 6 before restimulation. Inhibition of the β-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+ (cluster of differentiation) intermediate monocyte subset compared with controls with essential hypertension (n=14). Ex vivo production of proinflammatory 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 suggests enrichment of the transcriptionally permissive chromatin mark H3K4me3 (trimethylation of lysine 4 on histone H3), indicative of in vivo training. CONCLUSIONS: Catecholamines induce long-lasting proinflammatory 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.
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 proinflammatory effects of noradrenaline and adrenaline can, in part, be explained by the induction of an immunologic 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 lipopolysaccharide on day 6, (nor)adrenaline-exposed cells showed increased TNF-α (tumor necrosis factor-α) production. This coincided with an increase in glycolysis and oxidative phosphorylation measured with Seahorse technology on day 6 before restimulation. Inhibition of the β-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 PHEOpatients (n=10), the peripheral blood cell composition showed a myeloid bias and an increase of the inflammatory CD14++CD16+ (cluster of differentiation) intermediate monocyte subset compared with controls with essential hypertension (n=14). Ex vivo production of proinflammatory cytokines was higher in PHEOpatients. 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 PHEOpatients; epigenetic profiling of the promoters of these genes suggests enrichment of the transcriptionally permissive chromatin mark H3K4me3 (trimethylation of lysine 4 on histone H3), indicative of in vivo training. CONCLUSIONS:Catecholamines induce long-lasting proinflammatory 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 PHEOpatients.
Authors: Marlies P Noz; Siroon Bekkering; Laszlo Groh; Tim Mj Nielen; Evert Jp Lamfers; Andreas Schlitzer; Saloua El Messaoudi; Niels van Royen; Erik Hjpg Huys; Frank Wmb Preijers; Esther Mm Smeets; Erik Hjg Aarntzen; Bowen Zhang; Yang Li; Manita Ej Bremmers; Walter Jfm van der Velden; Harry Dolstra; Leo Ab Joosten; Marc E Gomes; Mihai G Netea; Niels P Riksen Journal: Elife Date: 2020-11-10 Impact factor: 8.140
Authors: Laszlo A Groh; Anaisa V Ferreira; Leonie Helder; Charlotte D C C van der Heijden; Boris Novakovic; Els van de Westerlo; Vasiliki Matzaraki; Simone J C F M Moorlag; L Charlotte de Bree; Valerie A C M Koeken; Vera P Mourits; Samuel T Keating; Jelmer H van Puffelen; Alexander Hoischen; Leo A B Joosten; Mihai G Netea; Werner J H Koopman; Niels P Riksen Journal: Immunometabolism Date: 2021-06-30