UC San Diego

Fingolimod is the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis (MS). Following phosphorylation in vivo, the active agent, fingolimod phosphate (fingolimod-P), acts as a sphingosine 1- phosphate (S1P) receptor modulator, binding with high affinity to four of the five known S1P receptors (S1P1, S1P3, S1P4 and S1P5). The mechanism of action of fingolimod in MS has primarily been considered as immunomodulatory, whereby fingolimod-P modulates S1P1 on lymphocytes, selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous system (CNS). However, emerging evidence indicates that fingolimod has direct effects in the CNS on MS relevant neural cell types including astrocytes, oligodendrocytes, neurons, and microglia. To study the roles of fingolimod and S1P signaling in MS, a transgenic activity reporter mouse was used in experimental autoimmune encephalomyelitis (EAE) to identify and characterize active cells during the disease process that may be altered by relevant S1P signaling. A subset of astrocytes is robustly activated at EAE sign onset in clusters that progressively expand along white matter tracts. The extent of astrocyte activation is highly correlated with disease severity and is limited by the loss of astrocytic S1P1. Transcriptome analyses of these EAE-activated astrocytes reveal several pathways that are both independently changed by astrocyte S1P1 knockouts and by fingolimod administration and concurrently changed by these S1P modulations. Among the pathways that have shared transcript differences in EAE-activated astrocytes from astrocyte S1P1 knockouts and by fingolimod administration, and control EAE-activated astrocytes, direct CNS effects of fingolimod may be uncovered.