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SLE Diagnosis
2001 α-ketoglutarate-dependent KDM6 histone demethylases epigenetically regulate Interferon Stimulated Gene expression in Lupus
  1. Erica N Montano1,2,
  2. Moumita Bose1,2,
  3. Lihong Huo1,2,
  4. Gantsetseg Tumurkhuu1,2,
  5. Gabriela De Los Santos1,2,
  6. Aleksandr B Stotland3,
  7. Janet Wei3,4,
  8. C Noel Bairey Merz3,
  9. Gislaine Martins2,5,6,
  10. Sarfaraz Lalani7,8,10,11,
  11. Kate Lawrenson7,8,9,10,11,
  12. Sarah Parker3,
  13. Mariko Ishimori1,11,
  14. Daniel J Wallace1,11 and
  15. Caroline Jefferies1,2,12
  1. 1Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA
  2. 2Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA
  3. 3Barbra Streisand Women’s Heart Center, Cedars-Sinai Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
  4. 4Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
  5. 5Department of Medicine, Division of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA
  6. 6F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute (IBIRI), Cedars-Sinai Medical Center, Los Angeles, CA
  7. 7Women’s Cancer Research Program at the Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  8. 8Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  9. 9Cancer Prevention and Control Program, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  10. 10Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  11. 11David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA
  12. 12Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Abstract

The authors have declared that no conflict of interest exists.

Objective To investigate the hypothesis that interferon (IFN) stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression.

Methods Monocytes from healthy volunteers and SLE patients at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation and gene expression.

Treatment of SLE monocytes or pristane-treated C57BL/6 mice with GSKJ4 assessed the effects of histone demethylases KDM6A/B on ISG expression.

Results Assessing differences in metabolic programing between monocytes isolated from healthy volunteers or SLE patients, we observed that SLE monocytes exhibit enhanced rates of glycolysis and oxidative phosphorylation, accompanied by an increase in isocitrate dehydrogenase (IDH2) and its product, α-KG. As IDH2 levels correlate with IFN-stimulated genes (ISG) expression, we hypothesized that IFNα priming of monocytes may be driving epigenetic changes at ISG promoters via increased α-KG. We observe decreased H3K27 trimethylation (repressive) and increased H3K4 trimethylation (permissive) at the promoters of ISGs, in keeping with the role α-KG plays as an obligate cofactor for histone demethylases KDM6A and KDM6B, which enhance gene expression by removing H3K27me3 marks at promoters.

Inhibition of KDM6A/B resulted in decreased ISG expression both in SLE patient monocytes and in a mouse model of IFN-driven lupus.

Conclusion Our study demonstrates the first link suggesting chronic IFNa/β exposure alters epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting innate immune memory or trained immunity to type I IFN. Importantly, it opens the possibility that drugs targeting histone modifying enzymes such as KDM6A/B may be effective in restoring homeostasis to the IFN network in SLE.

  • SLE
  • monocytes
  • IDH2
  • histone demethylation
  • interferon stimulated genes
  • trained immunity
  • immunometabolism
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

http://dx.doi.org/10.1136/lupus-2022-lupus21century.106

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