Uticaj donora vodonik-sulfida, morfolin-4-ium- 4-metoksifenil (morfolino)-fosfoditionata, na karakteristike imunskih ćelija uključenih u patogenezu eksperimentalnog autoimunskog encefalomijelitisa
Effects of hydrogen-sulfide donor, morpholin-4-ium 4-methoxyphenyl (morpholino) phosphinodithioate, on immune cells involved in experimental autoimmune encephalomyelitis pathogenesis
Abstract:
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, neurodegenerative disease of the central nervous system. The aim of this doctoral dissertation has been to improve knowledge about factors that influence MS pathogenesis and to define new potential MS therapeutics by examination of the effects of slow-releasing hydrogen-sulfide donor, GYY4137, on immune cells involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), commonly used MS animal model. Immunomodulatory effect of in vitro treatment with GYY4137 was investigated on BV2 cells (microglial cell line) and dendritic cells (DC) differentiated from bone marrow precursors of C57BL/6 mice. GYY4137 exerted potent anti-inflammatory effects on BV2 cells, while its effects on DC were limited. Further, GYY4137 effect on the percentage of different T cell subpopulations among cells isolated from popliteal lymph nodes (PLN) or spinal cords of immunized C57BL/6 mice and/or DA rats was evaluated. The results showed that, despite having no effect on the percentage of two major pathogenic T helper (Th) cell populations in EAE (Th1 and Th17 cells) among cells from PLN, GYY4137 reduced the percentage of Th17 among immune cells isolated from spinal cords of immunized rats. In contrast to the effect on the percentage of Th17 cells, GYY4137 reduced the percentage of regulatory T cells (Treg) among PLN cells, but not among immune cells obtained from spinal cords of immunized rats. GYY4137 accomplished its effect on the Treg percentage by reducing the relative protein expression of FoxP3, which was probably mediated by stimulation of its proteasomal degradation. Furthermore, GYY4137 potentiated reactive oxygen species generation in BV2 cells and CD4+ T cells isolated from PLN of immunized mice. The results of this doctoral thesis indicate that GYY4137 exerts immunomodulatory effects on immune cells involved in EAE pathogenesis, while the nature and intensity of these effects depend on the cell type and the milieu of cellular origin. Also, these results suggest that GYY4137 has a significant anti-encephalitogenic potential.
Keywords:
GYY4137; experimental autoimmune encephalomyelitis; multiple sclerosis; hydrogen-sulfide; T cells; microglia; dendritic cellsSource:
Faculty of Biology, University of Belgrade, 2021, 1-109Funding / projects:
- Cellular and molecular mechanisms of recovery of rats from experimental autoimmune encephalomyelitis (RS-MESTD-Basic Research (BR or ON)-173035)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)