Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

TY - JOUR

T1 - Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

AU - Srinivasan, Sundararajan

AU - Severa, Martina

AU - Rizzo, Fabiana

AU - Menon, Ramesh

AU - Brini, Elena

AU - Mechelli, Rosella

AU - Martinelli, Vittorio

AU - Hertzog, Paul

AU - Salvetti, Marco

AU - Furlan, Roberto

AU - Martino, Gianvito

AU - Comi, Giancarlo

AU - Coccia, Eliana M.

AU - Farina, Cinthia

N1 - Funding Information: We are grateful to all the participants who donated blood for this study and to Linda Ottoboni and Phil De Jager for providing additional information about the dataset described in8. This study was supported by Fondazione Italiana Sclerosi Multipla FISM (Grant 2013/R/9), Italian Ministry for Health (RF-2011-02349698) and Merck-Serono. Funding Information: Competing Interests: Sundararajan Srinivasan, Martina Severa, Fabiana Rizzo, Ramesh Menon, Elena Brini, Rosella Mechelli, Paul Hertzog, Eliana Coccia declare no conflict of interest. Vittorio Martinelli received speaking honoraria, consultancy fee and travel support from Bayer, Biogen-Idec, Merck-Serono, Novartis, Genzyme and Teva. Marco Salvetti received lecture fees and research support from Biogen, Bayer-Schering, Biogen-Dompé, Merck-Serono, Sanofi-Aventis, Teva. Roberto Furlan received speaker honoraria from Merck Serono, Novartis and Roche, and research support from EMD Serono. Gianvito Martino received speaker honoraria from Biogen Idec, Merck Serono; travel and research support from Merck Serono, Teva. Giancarlo Comi received speaker honoraria, consultancy fees from Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Receptors and Forward Pharm. Cinthia Farina received research support from Merck-Serono, Teva, Novartis. Publisher Copyright: © 2017 The Author(s).

PY - 2017/8/21

Y1 - 2017/8/21

N2 - Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription. Further, the analysis of almost 500 human blood transcriptomes showed that (i) several IRG changed expression at distinct MS stages with a core of 21 transcripts concordantly dysregulated in all MS forms compared with healthy subjects; (ii) 100 differentially expressed IRG were validated in independent case-control cohorts; and (iii) 53 out of 100 dysregulated IRG were targeted by IFN-beta treatment in vivo. Finally, ex vivo and in vitro experiments established that IFN-beta administration modulated expression of two IRG, ARRB1 and CHP1, in immune cells. Our study confirms the impairment of Interferome in experimental and human MS, and describes IRG signatures at distinct disease stages which can represent novel therapeutic targets in MS.

AB - Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription. Further, the analysis of almost 500 human blood transcriptomes showed that (i) several IRG changed expression at distinct MS stages with a core of 21 transcripts concordantly dysregulated in all MS forms compared with healthy subjects; (ii) 100 differentially expressed IRG were validated in independent case-control cohorts; and (iii) 53 out of 100 dysregulated IRG were targeted by IFN-beta treatment in vivo. Finally, ex vivo and in vitro experiments established that IFN-beta administration modulated expression of two IRG, ARRB1 and CHP1, in immune cells. Our study confirms the impairment of Interferome in experimental and human MS, and describes IRG signatures at distinct disease stages which can represent novel therapeutic targets in MS.

KW - Adult

KW - Aged

KW - Animals

KW - Blood Cells/immunology

KW - CD4-Positive T-Lymphocytes/immunology

KW - Case-Control Studies

KW - Central Nervous System/pathology

KW - Encephalomyelitis, Autoimmune, Experimental/pathology

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Immunologic Factors/biosynthesis

KW - Interferons/biosynthesis

KW - Male

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Multiple Sclerosis/pathology

KW - Young Adult

UR - https://www.scopus.com/pages/publications/85029393675

U2 - 10.1038/s41598-017-09286-y

DO - 10.1038/s41598-017-09286-y

M3 - Article

C2 - 28827704

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

M1 - 8981

ER -