Glycolytic reprogramming shapes the histone acetylation profile of activated CD4+ T cells in juvenile idiopathic arthritis

Enric Mocholi; Edward Corrigan; Theo Chalkiadakis; Can Gulersonmez; Edwin Stigter; Bas Vastert; Jorg van Loosdregt; Stefan Prekovic; Paul J Coffer

doi:10.1016/j.celrep.2025.115287

Glycolytic reprogramming shapes the histone acetylation profile of activated CD4⁺ T cells in juvenile idiopathic arthritis

Cell Rep. 2025 Feb 18;44(2):115287. doi: 10.1016/j.celrep.2025.115287. Online ahead of print.

Authors

Enric Mocholi¹, Edward Corrigan², Theo Chalkiadakis³, Can Gulersonmez³, Edwin Stigter³, Bas Vastert⁴, Jorg van Loosdregt⁵, Stefan Prekovic³, Paul J Coffer⁶

Affiliations

¹ Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: emocholi@uchceu.es.
² Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands.
³ Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
⁴ Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵ Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
⁶ Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: pcoffer@umcutrecht.nl.

PMID: 40009514
DOI: 10.1016/j.celrep.2025.115287

Abstract

Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by accumulation of activated CD4⁺ T cells in the synovial fluid (SF) of affected joints. JIA CD4⁺ T cells exhibit a unique inflammation-associated epigenomic signature, but the underlying mechanisms remain unclear. We demonstrate that CD4⁺ T cells from JIA SF display heightened glycolysis upon activation and JIA-specific H3K27 acetylation, driving transcriptional reprogramming. Pharmacological inhibition of glycolysis altered the expression of genes associated with these acetylated regions. Healthy CD4⁺ T cells exposed to JIA SF exhibited increased glycolytic activity and transcriptomic changes marked by heightened histone 3 lysine 27 acetylation (H3K27ac) at JIA-specific genes. Elevated H3K27ac was dependent on glycolytic flux, while inhibiting glycolysis or pyruvate dehydrogenase (PDH) impaired transcription of SF-driven genes. These findings demonstrate a key role of glycolysis in JIA-specific gene expression, offering potential therapeutic targets for modulating inflammation in JIA.

Keywords: CP: Immunology; CP: Metabolism; T cells; autoimmune disease; glucose metabolism; histone acetylation; juvenile idiopathic arthritis; pyruvate dehydrogenase.