Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia
Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point medi...
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doaj-6250e2956dfb4d0bba8f0bb0a59464cb2021-03-22T12:48:52ZengElsevierNeurobiology of Disease1095-953X2020-02-01134Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microgliaIvan Pilipović0Zorica Stojić-Vukanić1Ivana Prijić2Nebojša Jasnić3Gordana Leposavić4Immunology Research Centre “Branislav Janković”, Institute of Virology, Vaccines and Sera “Torlak”, 458 Vojvode Stepe, 11221 Belgrade, SerbiaDepartment of Microbiology and Immunology, University of Belgrade-Faculty of Pharmacy, 450 Vojvode Stepe, 11221 Belgrade, SerbiaImmunology Research Centre “Branislav Janković”, Institute of Virology, Vaccines and Sera “Torlak”, 458 Vojvode Stepe, 11221 Belgrade, SerbiaInstitute for Physiology and Biochemistry, University of Belgrade-Faculty of Biology, Studentski trg 16, 11000 Belgrade, SerbiaDepartment of Pathobiology, University of Belgrade-Faculty of Pharmacy, 450 Vojvode Stepe, 11221 Belgrade, Serbia; Corresponding author.Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point mediator, in modulation of microglial phenotypic and functional properties in rat EAE model was examined. The study showed that noradrenaline acting in neurocrine and autocrine/paracrine way might influence microglia during EAE. Propranolol treatment over the effector phase moderated EAE course. This was associated with the increased proportion of microglia expressing CX3CR1, the key molecule in their immunomodulatory/neuroprotective action, and upregulation of CX3CR1 downstream Nrf2 gene. This correlated with the increased heme oxygenase-1 (HO-1) expression and phagocytic capacity of microglia, and their phenotypic changes mirrored in increased proportion of CD163- and CD83-expressing cells. The enhanced HO-1 expression was linked with the decreased proportion of microglial cells expressing IL-1β and IL-23, and possibly IL-6, followed by increased proportion of IL-10–expressing microglia, and downregulated MCP-1/CCL2 expression. Consistently, spinal cord infiltration with blood-borne myeloid and CD4+ T cells, as well as CD4+ T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF were decreased in propranolol-treated rats compared with saline-injected controls. The in vitro investigations of the effects of noradrenaline on microglia showed that noradrenaline through β-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests β-adrenoceptor–mediated neuroinflammation-promoting role of noradrenaline in EAE via modulation of microglial Nrf2 expression, and thereby forms the basis for further translational pharmacological research to improve multiple sclerosis therapy.http://www.sciencedirect.com/science/article/pii/S0969996119303407Experimental autoimmune encephalomyelitisNoradrenalineβ-AdrenoceptorMicrogliaCX3CR1Nrf2/HO-1 axis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ivan Pilipović Zorica Stojić-Vukanić Ivana Prijić Nebojša Jasnić Gordana Leposavić |
spellingShingle |
Ivan Pilipović Zorica Stojić-Vukanić Ivana Prijić Nebojša Jasnić Gordana Leposavić Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia Neurobiology of Disease Experimental autoimmune encephalomyelitis Noradrenaline β-Adrenoceptor Microglia CX3CR1 Nrf2/HO-1 axis |
author_facet |
Ivan Pilipović Zorica Stojić-Vukanić Ivana Prijić Nebojša Jasnić Gordana Leposavić |
author_sort |
Ivan Pilipović |
title |
Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia |
title_short |
Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia |
title_full |
Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia |
title_fullStr |
Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia |
title_full_unstemmed |
Propranolol diminished severity of rat EAE by enhancing immunoregulatory/protective properties of spinal cord microglia |
title_sort |
propranolol diminished severity of rat eae by enhancing immunoregulatory/protective properties of spinal cord microglia |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2020-02-01 |
description |
Sympathetic dysfunction is suggested to contribute to development of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) alike. Considering important role of microglia in development/resolution of neuroinflammation, contribution of noradrenaline, the key sympathetic end-point mediator, in modulation of microglial phenotypic and functional properties in rat EAE model was examined. The study showed that noradrenaline acting in neurocrine and autocrine/paracrine way might influence microglia during EAE. Propranolol treatment over the effector phase moderated EAE course. This was associated with the increased proportion of microglia expressing CX3CR1, the key molecule in their immunomodulatory/neuroprotective action, and upregulation of CX3CR1 downstream Nrf2 gene. This correlated with the increased heme oxygenase-1 (HO-1) expression and phagocytic capacity of microglia, and their phenotypic changes mirrored in increased proportion of CD163- and CD83-expressing cells. The enhanced HO-1 expression was linked with the decreased proportion of microglial cells expressing IL-1β and IL-23, and possibly IL-6, followed by increased proportion of IL-10–expressing microglia, and downregulated MCP-1/CCL2 expression. Consistently, spinal cord infiltration with blood-borne myeloid and CD4+ T cells, as well as CD4+ T-cell reactivation/proliferation and differentiation into highly pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF were decreased in propranolol-treated rats compared with saline-injected controls. The in vitro investigations of the effects of noradrenaline on microglia showed that noradrenaline through β-adrenoceptor may influence Nrf2 expression also via CX3CR1-independent route. The study suggests β-adrenoceptor–mediated neuroinflammation-promoting role of noradrenaline in EAE via modulation of microglial Nrf2 expression, and thereby forms the basis for further translational pharmacological research to improve multiple sclerosis therapy. |
topic |
Experimental autoimmune encephalomyelitis Noradrenaline β-Adrenoceptor Microglia CX3CR1 Nrf2/HO-1 axis |
url |
http://www.sciencedirect.com/science/article/pii/S0969996119303407 |
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