Značaj signalizacije posredovane vanćelijskim purinskim nukleotidima u neuroinflamaciji i demijelinizaciji - implikacije u multiploj sklerozi
The role of purinergic signaling in neuroinflammation and demyelination – implications for multiple sclerosis
Doctoral thesis (Published version)
MetadataShow full item record
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that is characterized like its in vivo model experimental autoimmune encephalomyelitis (EAE) by immune cell infiltration, microglia and astrocyte activation, demyelination, axonal damage, as well as remyelination guided by oligodendrocyte progenitor cells (OPC). During neuroinflammation, ATP acts pro-, while adenosine acts anti-inflammatory via P2 and P1 purine receptors, respectively. Activation of specific purine receptor depends on ATP, ADP and adenosine extracellular concentrations that are regulated by by ectonucleotidases. In the CNS most abundant ectonucleotidases are NTPDase1/CD39, NTPDase2 and eN/CD73. Role of NTPDase1/CD39 and eN/CD73 in the cells of immune system, unlike in the CNS, in MS/EAE is mostly well known,. Since activated microglia and astrocytes have a key role in the course of neuroinflammation, the main goal of this dissertation was to study expression of major ectonucleotidases in the CNS at these cells and to assess their inflammatory phenotype, likewise to analyze expression of purine receptors in the rat spinal cord during EAE as animal model of MS. Considering role of OPC in remyelination during MS/EAE, additional goal was to assess the effects of proinflammatory factors at viability and functionality of OPC Oli-neu cell line and their expression of eN/CD73. Results presented herein have demonstrated disease phase-specific changes of all analyzed components of purine signaling system in rat spinal cord during EAE. Upregulation of NTPDase1/CD39 during EAE arised as a consequence of microglial activation and infiltration of monocytes/macrophages and other perypheral immune cells and also was related to transition of microglia/macrophages towards anti-inflammatory phenotype, likewise to induction of astrocyte polarization towards neuroprotective phenotype. Regarding NTPDase2, mainly expressed at white matter astrocytes, observed downregulation resulted from decreased expression by these cells during EAE. Additionally, during EAE all analyzed purine receptors showed phase-specific expression changes. Proinflammatory factors induced in OPC Oli-neu cell line upregulation of eN/CD73, indicating inhibition of differentiation, and arguing in favor of inhibitory effect of proinflammatory factors, present in the CNS during neuroinflammation, at OPC differentiation and remyelination during EAE/MS, likewise the role of eN/CD73 in that process. Thus, results presented herein indicate important role of major CNS ectonucleotidases in the disease course during EAE/MS, representing a base for development of new potential therapeutics.
Keywords:Multiple sclerosis/MS; Experimental autoimmune encephalomyelitis/EAE; ATP; NTPDase1/CD39; NTPDase2; eN/CD73; Neuroinflammation; Microglia; Astrocytes; Oligodendrocyte progenitor cells/OPC
Source:University of Belgrade, Faculty of Biology, 2020, 1-137
- Cellular and molecular basis of neuroinflamation: potential targets for translational medicine and therapy (RS-41014)