title: Differential effects of sympathetic nervous system and hypothalamic-pituitary-adrenal axis on systemic immune cells after severe experimental stroke.
abstract: Infectious complications are the leading cause of death in the post-acute phase of stroke. Post-stroke immunodeficiency is believed to result from neurohormonal dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. However, the differential effects of these neuroendocrine systems on the peripheral immune cells are only partially understood. Here, we determined the impact of the hormones of the SNS and HPA on distinct immune cell populations and characterized their interactions after stroke. At various time points after cortical or extensive hemispheric cerebral ischemia, plasma cortisone, corticosterone, metanephrine and adrenocorticotropic hormone (ACTH) levels were measured in mice. Leukocyte subpopulations were flow cytometrically analyzed in spleen and blood. To investigate their differential sensitivity to stress hormones, splenocytes were incubated in vitro with prednisolone, epinephrine and their respective receptor blockers. Glucocorticoid receptor (GCR) and beta2-adrenergic receptor (β2-AR) on leukocyte subpopulations were quantified by flow cytometry. In vivo effects of GCR and selective β2-AR blockade, respectively, were defined on serum hormone concentrations, lymphopenia and interferon-γ production after severe ischemia. We found elevated cortisone, corticosterone and metanephrine levels and associated lymphocytopenia only after extensive brain infarction. Prednisolone resulted in a 5 times higher cell death rate of splenocytes than epinephrine in vitro. Prednisolone and epinephrine-induced leukocyte cell death was prevented by GCR and β2-AR blockade, respectively. In vivo, only GCR blockade prevented post ischemic lymphopenia whereas β2-AR preserved interferon-γ secretion by lymphocytes. GCR blockade increased metanephrine levels in vivo and prednisolone, in turn, decreased β2-AR expression on lymphocytes. In conclusion, mediators of the SNS and the HPA axis differentially affect the systemic immune system after stroke. Moreover, our findings suggest a negative-feedback of corticosteroids on the sympathetic axis which may control the post-stroke stress-reaction. This complex interplay between the HPA and the SNS after stroke has to be considered when targeting the neurohormonal systems in the post acute phase of severe stroke.
authors.affiliation: Department of Neurology, University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Mracsko
authors.affiliation: Department of Neurology, University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Institute for Stroke and Dementia Research, University Hospital Munich, Max-Lebsche-Platz 30, 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Arthur
authors.initials: A
authors.lastname: Liesz
authors.affiliation: Department of Neurology, University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Karcher
authors.affiliation: Department of Internal Medicine and Laboratory Medicine, University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zorn
authors.affiliation: Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Bari
authors.affiliation: Department of Neurology, University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; Division of Brain Sciences, Imperial College, London, UK. Electronic address: Roland.Veltkamp@med.uni-heidelberg.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Veltkamp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood; D003348:Cortisone / Q000097:blood; D004837:Epinephrine / Q000494:pharmacology; D025461:Feedback, Physiological; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D020244:Infarction, Middle Cerebral Artery / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D007371:Interferon-gamma / Q000096:biosynthesis; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008231:Lymphopenia / Q000209:etiology; D008297:Male; D008676:Metanephrine / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D011239:Prednisolone / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000096:biosynthesis / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000037:antagonists & inhibitors; D013564:Sympathetic Nervous System / Q000503:physiopathology*
chemical_list: D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; C026777:ICI 118551; D008676:Metanephrine; D007371:Interferon-gamma; D011239:Prednisolone; D003348:Cortisone; D003345:Corticosterone; D004837:Epinephrine
keywords: Catecholamines; Glucocorticoids; Lymphocytes; Stroke-induced immunosuppression