Lupus & antiphospholipid syndrome
α‐Ketoglutarate–Dependent KDM6 Histone Demethylases and Interferon‐Stimulated Gene Expression in Lupus
Authors' conclusion
Our study suggests long-term IFNα exposure alters the epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN.
Study context
- Population
- Monocytes from healthy volunteers and patients with systemic lupus erythematosus (SLE); pristane and R848 mouse models of interferon (IFN)-driven SLE
- Comparison
- SLE vs healthy control monocytes; IFNα priming; KDM6A/B inhibition with glycogen synthase kinase J4 (GSK-J4)
Methodological detailshuman monocytes and mouse models (pristane and R848)
- Human monocytes and mouse models (pristane and R848)
Main finding
As reported in the abstract
- SLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation vs healthy control monocytes, and increased isocitrate dehydrogenase and α-KG
- IFNα priming (day 1) caused a sustained increase in ISG expression in primed cells (day 5) and enhanced expression on restimulation with IFNα
- Decreased H3K27 trimethylation at ISG promoters after IFNα priming
- GSK-J4 (KDM6A/B inhibitor) decreased ISG expression in SLE monocytes
- GSK-J4 reduced autoantibody production, ISG expression and kidney pathology in R848-treated BALB/c mice
Original publication
α‐Ketoglutarate–Dependent KDM6 Histone Demethylases and Interferon‐Stimulated Gene Expression in Lupus. Arthritis Rheumatol. Published 11 January 2024. doi:10.
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