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Open Access 01-12-2017

Fingolimod induces neuronal-specific gene expression with potential neuroprotective outcomes in maturing neuronal progenitor cells exposed to HIV

Authors: Rebeca Geffin, Ricardo Martinez, Alicia de las Pozas, Biju Issac, Micheline McCarthy

Published in: Journal of NeuroVirology | Issue 6/2017

Abstract

Fingolimod (FTY720), a structural analogue of sphingosine, targets sphingosine-1-phosphate receptor signaling and is currently an immunomodulatory therapy for multiple sclerosis. Fingolimod accesses the central nervous system (CNS) where its active metabolite, fingolimod phosphate (FTY720-P), has pleotropic neuroprotective effects in an inflammatory microenvironment. To investigate potential neuronal-specific mechanisms of fingolimod neuroprotection, we cultured the human neuronal progenitor cell line, hNP1, in differentiation medium supplemented with HIV- or Mock-infected supernatants, with or without FTY720-P. Gene expression was investigated using microarray and functional genomics. FTY720-P treatment increased differentially expressed (DE) neuronal genes by 33% in HIV-exposed and 40% in Mock-exposed cultures. FTY720-P treatment broadened the functional profile of DE genes in HIV-exposed versus Mock-exposed neurons, including not only immune responses but also transcriptional regulation and cell differentiation, among others. FTY720-P treatment downregulated the gene for follistatin, the antagonist of activin signaling, in all culture conditions. FTY720-P treatment differentially affected both glycolysis-related and immune response genes in Mock- or HIV-exposed cultures, significantly upregulating 11 glycolysis-related genes in HIV-exposed neurons. FTY720-P treatment also differentially upregulated genes related to innate immune responses and antigen presentation in Mock-exposed and more so in HIV-exposed neurons. However, in HIV-exposed neurons, FTY720-P depressed the magnitude of differential expression in almost half the genes, suggesting an anti-inflammatory potential. Moreover, in HIV-exposed neurons, FTY720-P reduced expression of the amyloid precursor protein (APP) gene, resulting in reduced expression of the APP protein. This study provides new evidence that fingolimod alters neuronal gene expression in inflammatory, viral-infected microenvironments, with the potential for neuroprotective effects.

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Title: Fingolimod induces neuronal-specific gene expression with potential neuroprotective outcomes in maturing neuronal progenitor cells exposed to HIV
Authors: Rebeca Geffin
Ricardo Martinez
Alicia de las Pozas
Biju Issac
Micheline McCarthy
Publication date: 01-12-2017
Publisher: Springer International Publishing
Published in: Journal of NeuroVirology / Issue 6/2017
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-017-0571-7

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Fingolimod induces neuronal-specific gene expression with potential neuroprotective outcomes in maturing neuronal progenitor cells exposed to HIV

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