Abstract
Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain. Impairments in the process of myelination, or demyelinating insults, might cause chronic diseases such as multiple sclerosis (MS). Under physiological conditions, remyelination is an ongoing process throughout adult life consisting in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs). During pathological events, this process fails due to unfavorable environment. Adenosine and sphingosine kinase/sphingosine 1-phosphate signaling axes (SphK/S1P) play important roles in remyelination processes. Remarkably, fingolimod (FTY720), a sphingosine analog recently approved for MS treatment, plays important roles in OPC maturation. We recently demonstrated that the selective stimulation of A2B adenosine receptors (A2BRs) inhibit OPC differentiation in vitro and reduce voltage-dependent outward K+ currents (IK) necessary to OPC maturation, whereas specific SphK1 or SphK2 inhibition exerts the opposite effect. During OPC differentiation A2BR expression increases, this effect being prevented by SphK1/2 blockade. Furthermore, selective silencing of A2BR in OPC cultures prompts maturation and, intriguingly, enhances the expression of S1P lyase, the enzyme responsible for irreversible S1P catabolism. Finally, the existence of an interplay between SphK1/S1P pathway and A2BRs in OPCs was confirmed since acute stimulation of A2BRs activates SphK1 by increasing its phosphorylation. Here the role of A2BR and SphK/S1P signaling during oligodendrogenesis is reviewed in detail, with the purpose to shed new light on the interaction between A2BRs and S1P signaling, as eventual innovative targets for the treatment of demyelinating disorders.
Highlights
In the central nervous system (CNS), oligodendrocytes (OLs) are responsible for myelin production, which allows fast signal transmission and provides metabolic support to axons (Nave, 2010; Saab et al, 2016)
The bioactive sphingosine 1-phosphate (S1P) selectively binds to high affinity cell surface G protein-coupled receptors (GPCRs; Sphingosine 1-phosphate receptor (S1PR)), named S1P1, S1P2, S1P3, S1P4, and S1P5 (Ishii et al, 2004) that have been involved in the majority of physiological and pathological actions evoked by S1P such as immune response, cardiovascular functions, cancer, atherosclerosis (Cartier and Hla, 2019) as well as multiple sclerosis (MS) (Strub et al, 2010; Maceyka et al, 2012)
Multiple evidences indicate that adenosine may interact with S1P signaling in orchestrating the processes concurring to oligodendrocyte progenitor cells (OPCs) maturation and to the remodeling of brain development and/or repair after a demyelinating insult
Summary
In the central nervous system (CNS), oligodendrocytes (OLs) are responsible for myelin production, which allows fast signal transmission and provides metabolic support to axons (Nave, 2010; Saab et al, 2016). OLs are generated in the germinal zones of the brain, i.e., the subventricular zone (SVZ) (Yu et al, 1994), from migratory bipolar oligodendrocyte precursor cells (OPCs), which are renowned for the expression of the proteoglycan nerve-glial antigen 2 (NG2) (Grinspan, 2002; Brazel et al, 2004) Thanks to their migratory ability, OPCs spread and populate the embryonic brain and spinal cord (Emery, 2010) to differentiate into myelinating OLs. a pool of immature OPCs, comprising the 5-8% of total glial cells (Levine et al, 2001), persists within the adult CNS where they represent the major population of cycling cells (Dawson et al, 2003). This review will focus on S1P and adenosine receptormediated effects in oligodendrocyte progenitors relevant for oligodendrogenesis and their possible functional interplay with the purpose to deepen the knowledge of molecular mechanisms involved in A2B receptor- (A2BR-) or S1P-mediated effects and their cross-talk in oligodendrocyte biology
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