Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

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

References

  1. Mavragani CP, Moutsopoulos HM (2014) Sjogren’s syndrome. Annu Rev Pathol 9:273–285

    Article  CAS  PubMed  Google Scholar 

  2. Ramos-Casals M, Brito-Zeron P, Siso-Almirall A, Bosch X (2012) Primary Sjogren syndrome. BMJ 344:e3821

    Article  PubMed  CAS  Google Scholar 

  3. Ramos-Casals M, Brito-Zeron P, Kostov B et al (2015) Google-driven search for big data in autoimmune geoepidemiology: analysis of 394,827 patients with systemic autoimmune diseases. Autoimmun Rev 14:670–679

    Article  PubMed  Google Scholar 

  4. Christodoulou MI, Kapsogeorgou EK, Moutsopoulos HM (2010) Characteristics of the minor salivary gland infiltrates in Sjogren’s syndrome. J Autoimmun 34:400–407

    Article  CAS  PubMed  Google Scholar 

  5. Mingueneau M, Boudaoud S, Haskett S, Reynolds TL, Nocturne G, Norton E, Zhang X, Constant M, Park D, Wang W, Lazure T, le Pajolec C, Ergun A, Mariette X (2016) Cytometry by time-of-flight immunophenotyping identifies a blood Sjogren’s signature correlating with disease activity and glandular inflammation. J Allergy Clin Immunol 137:1809–1821 e1812

    Article  PubMed  Google Scholar 

  6. Nair JJ, Singh TP (2017) Sjogren’s syndrome: review of the aetiology, pathophysiology & potential therapeutic interventions. J Clin Exp Dent 9:e584–e589

    PubMed  PubMed Central  Google Scholar 

  7. Brito-Zeron P, Kostov B, Solans R et al (2016) Systemic activity and mortality in primary Sjogren syndrome: predicting survival using the EULAR-SS disease activity index (ESSDAI) in 1045 patients. Ann Rheum Dis 75:348–355

    Article  CAS  PubMed  Google Scholar 

  8. Bowman SJ (2018) Primary Sjogren’s syndrome. Lupus 27:32–35

    Article  CAS  PubMed  Google Scholar 

  9. Brkic Z, Maria NI, van Helden-Meeuwsen CG, van de Merwe JP, van Daele PL, Dalm VA, Wildenberg ME, Beumer W, Drexhage HA, Versnel MA (2013) Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren’s syndrome and association with disease activity and BAFF gene expression. Ann Rheum Dis 72:728–735

    Article  CAS  PubMed  Google Scholar 

  10. Hall JC, Casciola-Rosen L, Berger AE, Kapsogeorgou EK, Cheadle C, Tzioufas AG, Baer AN, Rosen A (2012) Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc Natl Acad Sci U S A 109:17609–17614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gottenberg JE, Cagnard N, Lucchesi C, Letourneur F, Mistou S, Lazure T, Jacques S, Ba N, Ittah M, Lepajolec C, Labetoulle M, Ardizzone M, Sibilia J, Fournier C, Chiocchia G, Mariette X (2006) Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjogren’s syndrome. Proc Natl Acad Sci U S A 103:2770–2775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Imgenberg-Kreuz J, Sandling JK, Almlof JC et al (2016) Genome-wide DNA methylation analysis in multiple tissues in primary Sjogren’s syndrome reveals regulatory effects at interferon-induced genes. Ann Rheum Dis 75:2029–2036

    Article  CAS  PubMed  Google Scholar 

  13. Hall JC, Baer AN, Shah AA, Criswell LA, Shiboski CH, Rosen A, Casciola-Rosen L (2015) Molecular subsetting of interferon pathways in Sjogren’s syndrome. Arthritis Rheum 67:2437–2446

    Article  CAS  Google Scholar 

  14. Altorok N, Coit P, Hughes T, Koelsch KA, Stone DU, Rasmussen A, Radfar L, Scofield RH, Sivils KL, Farris AD, Sawalha AH (2014) Genome-wide DNA methylation patterns in naive CD4+ T cells from patients with primary Sjogren’s syndrome. Arthritis Rheum 66:731–739

    Article  CAS  Google Scholar 

  15. Cole MB, Quach H, Quach D, Baker A, Taylor KE, Barcellos LF, Criswell LA (2016) Epigenetic signatures of salivary gland inflammation in Sjogren’s syndrome. Arthritis Rheum 68:2936–2944

    Article  CAS  Google Scholar 

  16. Miceli-Richard C, Wang-Renault SF, Boudaoud S, Busato F, Lallemand C, Bethune K, Belkhir R, Nocturne G, Mariette X, Tost J (2016) Overlap between differentially methylated DNA regions in blood B lymphocytes and genetic at-risk loci in primary Sjogren’s syndrome. Ann Rheum Dis 75:933–940

    Article  CAS  PubMed  Google Scholar 

  17. Charras A, Konsta OD, Le Dantec C et al (2017) Cell-specific epigenome-wide DNA methylation profile in long-term cultured minor salivary gland epithelial cells from patients with Sjogren's syndrome. Ann Rheum Dis 76:625–628

    Article  CAS  PubMed  Google Scholar 

  18. Konsta OD, Charras A, Le Dantec C et al (2016) Epigenetic modifications in salivary glands from patients with Sjogren’s syndrome affect cytokeratin 19 expression. Bull Group Int Rech Sci Stomatol Odontol 53:e01

    CAS  PubMed  Google Scholar 

  19. Konsta OD, Le Dantec C, Charras A et al (2016) Defective DNA methylation in salivary gland epithelial acini from patients with Sjogren’s syndrome is associated with SSB gene expression, anti-SSB/LA detection, and lymphocyte infiltration. J Autoimmun 68:30–38

    Article  CAS  PubMed  Google Scholar 

  20. Lagos C, Carvajal P, Castro I, Jara D, González S, Aguilera S, Barrera MJ, Quest AFG, Bahamondes V, Molina C, Urzúa U, Hermoso MA, Leyton C, González MJ (2018) Association of high 5-hydroxymethylcytosine levels with ten eleven translocation 2 overexpression and inflammation in Sjogren’s syndrome patients. Clin Immunol 196:85–96

    Article  CAS  PubMed  Google Scholar 

  21. Thabet Y, Le Dantec C, Ghedira I et al (2013) Epigenetic dysregulation in salivary glands from patients with primary Sjogren’s syndrome may be ascribed to infiltrating B cells. J Autoimmun 41:175–181

    Article  CAS  PubMed  Google Scholar 

  22. Lu Q, Renaudineau Y, Cha S, Ilei G, Brooks WH, Selmi C, Tzioufas A, Pers JO, Bombardieri S, Gershwin ME, Gay S, Youinou P (2010) Epigenetics in autoimmune disorders: highlights of the 10th Sjogren’s syndrome symposium. Autoimmun Rev 9:627–630

    Article  PubMed  Google Scholar 

  23. Rasmussen KD, Helin K (2016) Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev 30:733–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kietzmann T, Petry A, Shvetsova A, Gerhold JM, Gorlach A (2017) The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system. Br J Pharmacol 174:1533–1554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gerber SA, Pober JS (2008) IFN-alpha induces transcription of hypoxia-inducible factor-1alpha to inhibit proliferation of human endothelial cells. J Immunol 181:1052–1062

    Article  CAS  PubMed  Google Scholar 

  26. Nelson J, Manzella K, Baker OJ (2013) Current cell models for bioengineering a salivary gland: a mini-review of emerging technologies. Oral Dis 19:236–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu Q, Ni X (2015) ROS-mediated DNA methylation pattern alterations in carcinogenesis. Curr Drug Targets 16:13–19

    Article  PubMed  CAS  Google Scholar 

  28. Smallwood MJ, Nissim A, Knight AR, Whiteman M, Haigh R, Winyard PG (2018) Oxidative stress in autoimmune rheumatic diseases. Free Radic Biol Med 125:3–14

    Article  CAS  PubMed  Google Scholar 

  29. Menezo YJ, Silvestris E, Dale B, Elder K (2016) Oxidative stress and alterations in DNA methylation: two sides of the same coin in reproduction. Reprod BioMed Online 33:668–683

    Article  CAS  PubMed  Google Scholar 

  30. Mavragani CP, Crow MK (2010) Activation of the type I interferon pathway in primary Sjogren’s syndrome. J Autoimmun 35:225–231

    Article  CAS  PubMed  Google Scholar 

  31. Bodewes ILA, Versnel MA (2018) Interferon activation in primary Sjogren’s syndrome: recent insights and future perspective as novel treatment target. Expert Rev Clin Immunol 14:817–829

    Article  CAS  PubMed  Google Scholar 

  32. Bordron A, Charras A, Le Dantec C, Renaudineau Y (2018) Influence of epigenetic in Sjogren’s syndrome. Rev Med Interne 39:346–351

    Article  CAS  PubMed  Google Scholar 

  33. Mavragani CP, Nezos A, Sagalovskiy I, Seshan S, Kirou KA, Crow MK (2018) Defective regulation of L1 endogenous retroelements in primary Sjogren’s syndrome and systemic lupus erythematosus: role of methylating enzymes. J Autoimmun 88:75–82

    Article  CAS  PubMed  Google Scholar 

  34. Simon AR, Rai U, Fanburg BL, Cochran BH (1998) Activation of the JAK-STAT pathway by reactive oxygen species. Am J Phys 275:C1640–C1652

    Article  CAS  Google Scholar 

  35. Di Dalmazi G, Hirshberg J, Lyle D, Freij JB, Caturegli P (2016) Reactive oxygen species in organ-specific autoimmunity. Auto Immun Highlights 7:11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Kaffe ET, Rigopoulou EI, Koukoulis GK, Dalekos GN, Moulas AN (2015) Oxidative stress and antioxidant status in patients with autoimmune liver diseases. Redox Rep 20:33–41

    Article  CAS  PubMed  Google Scholar 

  37. Ke Y, Xu X, Mei S, Xie X, Tao G (2014) The association of DNA methylation and DNA oxidation induced by H2O2. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 32:50–54

    CAS  PubMed  Google Scholar 

  38. Fan G, Martinowich K, Chin MH, He F, Fouse SD, Hutnick L, Hattori D, Ge W, Shen Y, Wu H, ten Hoeve J, Shuai K, Sun YE (2005) DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132:3345–3356

    Article  CAS  PubMed  Google Scholar 

  39. Zhang Q, Wang HY, Woetmann A, Raghunath PN, Odum N, Wasik MA (2006) STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes. Blood 108:1058–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pan Z, Xue Z-Y, Li G-F, Sun ML, Zhang M, Hao LY, Tang QQ, Zhu LJ, Cao JL (2017) DNA hydroxymethylation by ten-eleven translocation methylcytosine dioxygenase 1 and 3 regulates nociceptive sensitization in a chronic inflammatory pain model. Anesthesiology: The Journal of the American Society of Anesthesiologists 127:147–163

    Article  CAS  Google Scholar 

  41. Brooks AJ, Dai W, O'Mara ML, Abankwa D, Chhabra Y, Pelekanos RA, Gardon O, Tunny KA, Blucher KM, Morton CJ, Parker MW, Sierecki E, Gambin Y, Gomez GA, Alexandrov K, Wilson IA, Doxastakis M, Mark AE, Waters MJ (2014) Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 344:1249783

    Article  PubMed  CAS  Google Scholar 

  42. Scott R, Siegrist F, Foser S, Certa U (2011) Interferon-alpha induces reversible DNA demethylation of the interferon-induced transmembrane protein-3 core promoter in human melanoma cells. J Interf Cytokine Res 31:601–608

    Article  CAS  Google Scholar 

  43. Pertovaara M, Silvennoinen O, Isomaki P (2016) Cytokine-induced STAT1 activation is increased in patients with primary Sjogren’s syndrome. Clin Immunol 165:60–67

    Article  CAS  PubMed  Google Scholar 

  44. Lee J, Lee J, Kwok SK, Baek SY, Jang SG, Hong SM, Min JW, Choi SS, Lee J, Cho ML, Park SH (2018) JAK-1 inhibition suppresses interferon-induced BAFF production in human salivary gland: potential therapeutic strategy for primary Sjogren’s syndrome. Arthritis Rheum 70:2057–2066

    Article  CAS  Google Scholar 

  45. Carballo M, Conde M, El Bekay R et al (1999) Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes. J Biol Chem 274:17580–17586

    Article  CAS  PubMed  Google Scholar 

  46. Qing Y, Stark GR (2004) Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J Biol Chem 279:41679–41685

    Article  CAS  PubMed  Google Scholar 

  47. Hillion S, Arleevskaya MI, Brooks WH et al (2019) The innate part of the adaptive immune system. Clin Rev Allerg Immunol. https://doi.org/10.1007/s12016-019-08740-1

  48. Guia S, Vivier E, Narni-Mancinelli E (2019) Helper-like innate lymphoid cells: definition, functions and clinical implications in inflammatory diseases and cancer. Clin Rev Allerg Immunol (in press)

  49. Grasseau A, Boudigou M, Le Pottier L et al (2019) Innate B-cells: the archetype of protective immune cells. Clin Rev Allerg Immunol. https://doi.org/10.1007/s12016-019-08748-7

    Article  Google Scholar 

  50. Brilland B, Scherlinger M, Khoryati L et al (2019) Platelets and IgE: shaping the innate immune response in systemic lupus erythematosus. Clin Rev Allerg Immunol. https://doi.org/10.1007/s12016-019-08744-x

  51. Maddur MS, Lacroix-Desmazes S, Dimitrov JD et al (2019) Natural antibodies: from first line defense against pathogens to perpetual immune homeostasis. Clin Rev Allerg Immunol. https://doi.org/10.1007/s12016-019-08746-9

  52. Defendia F, Thielensb NM, Clavarinoa G, Cesbron JY, Dumestre-Pérard C (2019) Autoantibodies targeting complement components and associated diseases. Clin Rev Allerg Immunol (in press)

  53. Bordron A, Bagacean C, Tempescul A et al (2019) Complement system: a neglected pathway in immunotherapy. Clin Rev Allerg Immunol. https://doi.org/10.1007/s12016-019-08741-0

  54. Arleevskaya MI, Larionova RV, Brooks WH, Bettacchioli E, Renaudineau Y (2019) Toll-like receptors, infections, and rheumatoid arthritis. Clin Rev Allerg Immunol. https://doi.org/10.1007/s12016-019-08742-z

  55. Larionova RV, Arleevskaya MI, Kravtsova OA, Validov S, Renaudineau Y (2019) In seroconverted rheumatoid arthritis patients a multi-reactive anti-herpes IgM profile is associated with disease activity. Clin Immunol 200:19–23

    Article  CAS  PubMed  Google Scholar 

  56. Arleevskaya MI, Albina S, Larionova RV, Gabdoulkhakova AG, Lemerle J, Renaudineau Y (2018) Prevalence and incidence of upper respiratory tract infection events are elevated prior to the development of rheumatoid arthritis in first-degree relatives. Front Immunol 9:2771

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Arleevskaya MI, Shafigullina AZ, Filina YV, Lemerle J, Renaudineau Y (2017) Associations between viral infection history symptoms, granulocyte reactive oxygen species activity, and active rheumatoid arthritis disease in untreated women at onset: results from a longitudinal cohort study of Tatarstan women. Front Immunol 8:1725

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Arleevskaya MI, Aminov R, Brooks WH, Manukyan G, Renaudineau Y (2019) Editorial: shaping oh human immune system and metabolic processes by viruses and microorganisms. Front Microbiol 10:816

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Author notes

  1. Amandine Charras, Pinelopi Arvaniti, Anne Bordon and Yves Renaudineau contributed equally to this work.

Authors and Affiliations

  1. University of Brest, UMR1227, B Lymphocytes B and Autoimmunity, Brest, France

    Amandine Charras, Christelle Le Dantec, Anne Bordon & Yves Renaudineau

  2. Laboratory of Immunology and Immunotherapy, CHU de Brest, France

    Pinelopi Arvaniti & Yves Renaudineau

  3. Institute of Internal Medicine and Hepatology, Larissa, Greece

    Pinelopi Arvaniti, Kaliopi Zachou & George N. Dalekos

  4. Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece

    Pinelopi Arvaniti, Kaliopi Zachou & George N. Dalekos

  5. Central Research Laboratory, Kazan Federal University, Kazan, Russia

    Marina I. Arleevskaya & Yves Renaudineau

Authors
  1. Amandine Charras
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pinelopi Arvaniti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christelle Le Dantec
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marina I. Arleevskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kaliopi Zachou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. George N. Dalekos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anne Bordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yves Renaudineau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yves Renaudineau.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Charras, A., Arvaniti, P., Le Dantec, C. et al. JAK Inhibitors Suppress Innate Epigenetic Reprogramming: a Promise for Patients with Sjögren’s Syndrome. Clinic Rev Allerg Immunol 58, 182–193 (2020). https://doi.org/10.1007/s12016-019-08743-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-019-08743-y

Keywords

Search

Navigation