@conference{
author = "Pilipović, Ivan and Prijić, Ivana and Stojić-Vukanić, Zorica and Leposavić, Gordana",
year = "2019",
abstract = "Sympathetic dysfunction was proposed to participate in development of multiple sclerosis and
its animal model, experimental autoimmune encephalomyelitis (EAE). This may be linked with
findings indicating that noradrenaline, the key sympathetic end-point mediator, through β adrenoceptor exerts immunomodulatory action. Considering importance of the target tissue for
the clinical outcome of EAE, the study investigated the effects of propranolol, a non-selective β adrenoceptor blocker, on the disease severity in Dark Agouti rats. Administration of propranolol
over the effector phase of EAE substantially moderated neurological symptoms of the disease.
This correlated with the increased proportion of spinal cord microglia expressing CX3CR1, the
crucial neuroinflammation-limiting molecule, and upregulated expression of Nrf2, the key
CX3CR1 downstream target gene. Additionally, in spinal cord of propranolol-administered rats
the expression of heme-oxigenase 1, Nrf2 target gene, was upregulated. Consequently, microglia
from propranolol-administered rats, exhibited increased proportion of IL-10–expressing cells,
but decreased those of IL-1β– and IL-23–expressing ones. Propranolol also downregulated the
IL-6 and MCP-1/CCL2 expression in spinal cord. Furthermore, propranolol affecting
CXCR1/Nrf2 signaling pathway enhanced microglial phagocytic/endocytic capacity and surface
expression of anti-inflammatory CD163/CD83 markers. Results from in vitro pharmacological
study examining influence of noradrenaline/propranolol on functional properties of microglia
showed that microglia synthesize noradrenaline, which, in turn, through β-adrenoceptor,
downregulated their Nrf2 expression, in a CX3CR1-independent manner. In accordance with
microglial shift towards a more anti-inflammatory profile, in spinal cord of propranolol administered rats was found: i) decreased infiltration with blood-borne myeloid and CD4+ T
cells, and ii) reduced CD4+ T-cell reactivation/proliferation and differentiation into highly
pathogenic IL-17+ cells co-producing IFN-γ and GM-CSF. The study suggests a
neuroinflammation-promoting role for central noradrenaline in EAE, via β-adrenoceptor–
mediated modulation of microglial Nrf2 expression. Thus, it points out to a putative target for
future translational pharmacological research to optimize multiple sclerosis therapy. Funding:
MPNTR RS (grant number 175050)",
publisher = "Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia, Immunological Society of Serbia",
journal = "Immunology at the confluence of multidisciplinary approaces, Belgrade December 6.-8. 2019, Abstract book",
title = "Propranolol reduced severity of EAE by increasing the expression Nrf2 in microglia",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5085"
}