The Selective Agonist for Sphingosine-1-Phosphate Receptors Siponimod Increases the Expression Level of NR4A Genes in Microglia Cell Line.

Francesca Montarolo,Marco Alfonso Capobianco,Fabiana Marnetto,Antonio Bertolotto,Sabdi Valverde,Serena Martire,Paola Valentino

doi:10.3390/cimb44030083

Francesca Montarolo, Marco Alfonso Capobianco + Show 5 more

Open Access

https://doi.org/10.3390/cimb44030083

Copy DOI

Abstract

Fingolimod (FTY720) and siponimod (BAF312) are selective agonists for sphingosine-1-phosphate (S1P) receptors approved for the treatment of relapsing–remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), respectively. BAF312 exerts pro-myelination and neuro-protective functions on CNS resident cells, although the underlying molecular mechanism is not yet fully understood. NR4A2 is an anti-inflammatory gene, belonging to the NR4A family, whose expression is reduced in blood from treatment-naïve patients with RRMS, but is restored in patients treated with FTY720 for more than two years. We performed an in vitro study to investigate the potential involvement of the NR4A genes in the protective and restorative effects of BAF312. We showed that BAF312 enhances the expression of NR4A1 and NR4A2 in the N9 microglial cell line, but has no effect in the peripheral blood mononuclear cells and oligodendrocytes. This study suggests a novel molecular mechanism of action for the selective agonists for S1P receptors within the CNS.

Highlights

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by demyelination and subsequent axonal damage [1], in which inflammation, lymphocyte/macrophage infiltration, and microglia activation play a key pathophysiological role [1]
FTY720 and BAF312 are characterized by different affinities for the S1P receptor subtypes, and while FTY720 was the first effective S1P receptor-modulating drug to be used in patients with RRMS, BAF312 was proven to be clinically effective in patients with active SPMS [2]
Besides the known immune-modulatory effects exerted through the induction of S1P1 internalization in lymphocytes, BAF312 has shown pro-myelination and neuro-protective effects due to the interaction with S1P1 and S1P5 on CNS resident cells [7–9]

Summary

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by demyelination and subsequent axonal damage [1], in which inflammation, lymphocyte/macrophage infiltration, and microglia activation play a key pathophysiological role [1]. Among a variety of disease-modifying therapies (DMTs) approved for the treatment of MS, the selective agonists for sphingosine-1-phosphate (S1P). Receptors, namely fingolimod (FTY720) and siponimod (BAF312), are a class of effective oral drugs [2]. FTY720 was the first S1P receptor modulator approved for the treatment of relapsing–remitting (RR) MS [4,5], and it was found to activate all S1P receptor subtypes, except for S1P2. BAF312 is a selective agonist for S1P1 and S1P5 [2]; in the USA, it was approved for the treatment of relapsing forms of MS, including clinically isolated syndrome, RRMS, and secondary progressive (SP) MS, and in Europe for SPMS with clinical/radiological evidence of disease activity

Methods

Results

Conclusion