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JAK Inhibitors Suppress Innate Epigenetic Reprogramming: a Promise for Patients with Sjögren’s Syndrome

  • Amandine Charras
  • Pinelopi Arvaniti
  • Christelle Le Dantec
  • Marina I. Arleevskaya
  • Kaliopi Zachou
  • George N. Dalekos
  • Anne Bordon
  • Yves RenaudineauEmail author
Article

Abstract

Pathogenesis of primary Sjögren’s syndrome (SjS) remains obscure. However, recent data demonstrate the implication of epigenetic alterations in the DNA methylation/hydroxymethylation process in SjS mostly affecting genes regulated by two innate cytokines, interferon α (IFNα) and IFNγ as well as the oxidative stress pathways. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway is known to be activated by IFN and reactive oxygen species (ROS). This prompts us to test the potential implication of JAK/STAT signaling on DNA methylation/hydroxymethylation alterations in SjS. For this purpose, the human salivary gland (HSG) cell line was used and cells were treated with both types of IFNs and H2O2 to mimic activated salivary gland epithelial cells (SGEC) as observed in SjS patients. Afterwards, the global DNA level of methylcytosine and hydroxymethylcytosine, the expression of the DNA methylating enzymes (DNMTs) and ten-eleven translocation (TETs) methyl cytosine dioxygenase that controls DNA hydroxymethylation, both at transcriptional and at protein level, as well as STAT phosphorylation and ROS status were determined. Our results showed that expression of TET3 and in turn global DNA hydroxymethylation is controlled through the induction of STAT3 mediated by IFNα, IFNγ, and H2O2. On the other hand, treatment with JAK inhibitors (AG490 and ruxolitinib) reverses this process, suggesting a novel treatment pathway for patients with autoimmune diseases and Sjögren’s syndrome.

Keywords

Sjögren’s syndrome DNA methylation/hydroxymethylation Interferon JAK-STAT pathway JAK inhibitors DNMTs TETs 

Abbreviations

SjS

Sjögren’s syndrome

IFN

Interferon

RA

Rheumatoid arthritis

SLE

Systemic lupus erythematosus

LB

Lymphocytes B

LT

Lymphocytes T

SGECs

Salivary gland epithelial cells

EWAS

Epigenome wide association studies

IFNAR

IFNα receptor

JAK

Janus activated kinase

STAT

Signal transducer and activator of transcription

MSG

Minor salivary gland

NK

Natural killer

DNMT

DNA methyltransferase

TET

Translocation methylcytosine dioxygenase

HSG

Human salivary gland cell line

H2O2

Oxygen peroxide

ROS

Reactive oxygen species

pSTAT1

Phosphorylated STAT1

pSTAT3

Phosphorylated STAT3

MFI

Mean fluorescence intensity

5hmC

5-Hydroxymethylcytosine

5mC

5-Methylcytosine

WB

Western blot

HIF-1

Hypoxia-induced factor-1

ISGs

Interferon-stimulated genes

Notes

Acknowledgments

We are thankful to Servier Medical for providing free art for the figures, and Genevieve Michel for secretarial help.

Funding

This study was supported by research funding from the “Russian Science Foundation” (No. 17-15-01099), the “Association Française de Gougerot Sjögren et des syndromes secs”, the “Ligue against cancer”, the Brittany region, and the Brest University Hospital INNOVEO donation fund.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Amandine Charras
    • 1
  • Pinelopi Arvaniti
    • 2
    • 3
    • 4
  • Christelle Le Dantec
    • 1
  • Marina I. Arleevskaya
    • 5
  • Kaliopi Zachou
    • 3
    • 4
  • George N. Dalekos
    • 3
    • 4
  • Anne Bordon
    • 1
  • Yves Renaudineau
    • 1
    • 2
    • 5
    Email author
  1. 1.University of Brest, UMR1227, B Lymphocytes B and AutoimmunityBrestFrance
  2. 2.Laboratory of Immunology and ImmunotherapyCHU de BrestFrance
  3. 3.Institute of Internal Medicine and HepatologyLarissaGreece
  4. 4.Department of Medicine and Research Laboratory of Internal MedicineUniversity Hospital of LarissaLarissaGreece
  5. 5.Central Research LaboratoryKazan Federal UniversityKazanRussia

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