Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

Sundararajan Srinivasan, Martina Severa, Fabiana Rizzo, Ramesh Menon, Elena Brini, Rosella Mechelli, Vittorio Martinelli, Paul Hertzog, Marco Salvetti, Roberto Furlan, Gianvito Martino, Giancarlo Comi, Eliana Coccia, Cinthia Farina

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number8981
Number of pages9
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

Cite this

Srinivasan, S., Severa, M., Rizzo, F., Menon, R., Brini, E., Mechelli, R., ... Farina, C. (2017). Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis. Scientific Reports, 7(1), [8981]. https://doi.org/10.1038/s41598-017-09286-y
Srinivasan, Sundararajan ; Severa, Martina ; Rizzo, Fabiana ; Menon, Ramesh ; Brini, Elena ; Mechelli, Rosella ; Martinelli, Vittorio ; Hertzog, Paul ; Salvetti, Marco ; Furlan, Roberto ; Martino, Gianvito ; Comi, Giancarlo ; Coccia, Eliana ; Farina, Cinthia. / Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
@article{a815a11259f5403bbdc019f559072488,
title = "Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis",
abstract = "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.",
author = "Sundararajan Srinivasan and Martina Severa and Fabiana Rizzo and Ramesh Menon and Elena Brini and Rosella Mechelli and Vittorio Martinelli and Paul Hertzog and Marco Salvetti and Roberto Furlan and Gianvito Martino and Giancarlo Comi and Eliana Coccia and Cinthia Farina",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-09286-y",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

Srinivasan, S, Severa, M, Rizzo, F, Menon, R, Brini, E, Mechelli, R, Martinelli, V, Hertzog, P, Salvetti, M, Furlan, R, Martino, G, Comi, G, Coccia, E & Farina, C 2017, 'Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis', Scientific Reports, vol. 7, no. 1, 8981. https://doi.org/10.1038/s41598-017-09286-y

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis. / Srinivasan, Sundararajan; Severa, Martina; Rizzo, Fabiana; Menon, Ramesh; Brini, Elena; Mechelli, Rosella; Martinelli, Vittorio; Hertzog, Paul; Salvetti, Marco; Furlan, Roberto; Martino, Gianvito; Comi, Giancarlo; Coccia, Eliana; Farina, Cinthia.

In: Scientific Reports, Vol. 7, No. 1, 8981, 01.12.2017.

Research output: Contribution to journalArticleResearchpeer-review

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

AU - Farina, Cinthia

PY - 2017/12/1

Y1 - 2017/12/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85029393675&partnerID=8YFLogxK

U2 - 10.1038/s41598-017-09286-y

DO - 10.1038/s41598-017-09286-y

M3 - Article

AN - SCOPUS:85029393675

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 8981

ER -