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Succinate drives gut inflammation by promoting FoxP3 degradation through a molecular switch

ABSTRACT: Succinate levels are elevated in inflammatory bowel disease (IBD), but its role in disease pathogenicity remains unknown. This study shows that succinate promotes colitis in mice by reducing FoxP3 expression in regulatory T cells (Tregs) and increasing IL-17. Succinate selectively reduced the expression of 2-oxoglutarate dehydrogenase complex (OGDHc), the enzyme for succinyl-CoA synthesis, which in turn reduced FoxP3 succinylation and made FoxP3 lysine residues available for ubiquitination and Foxp3 protein degradation. Genetic deletion of Dlst, a member of OGDHc, in Tregs led to reduced FoxP3, impaired Treg function, and severe gut inflammation. Restoring FoxP3 fully rescued Dlst-deficient Treg immune suppressive functions. In IBD patients, FoxP3 and OGDHc levels were reduced in Tregs and negatively correlated with succinate levels and inflammation severity. This study identifies succinate as a pathogenic factor in IBD, uncovering a succinate-driven molecular switch that regulates FoxP3 stability and Treg function during inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE277632 | GEO | 2025/04/11

REPOSITORIES: GEO

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Loss of Foxp3-driven epigenetic modification leads to regulatory T cell insufficiency

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Project description:The proposed use of Foxp3+ T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmune diseases, or post-hemopoietic stem cell or organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3 expression. Conserved CpG dinucleotides in the Treg-specific demethylated region (TSDR) upstream of Foxp3 are demethylated only in stable, thymic-derived Foxp3+ Tregs. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling complexes to methylated sites, we tested whether targeting of Mbd2 might promote demethylation of Foxp3 and thereby promote Treg numbers or function. Surprisingly, while ChIP analysis showed Mbd2 binding to the Foxp3-associated TSDR site in Tregs, Mbd2 targeting by homologous recombination or siRNA decreased Treg numbers and impaired Treg suppressive function in vitro and in vivo. Moreover, we found complete TSDR demethylation in WT Tregs but >75% methylation in Mbd2-/- Tregs, whereas re-introduction of Mbd2 into Mbd2-null Tregs restored TSDR demethylation, Foxp3 gene expression and Treg suppressive function. Lastly, Mbd2-/- Tregs had markedly binding of the DNA demethylase enzyme, Tet2, in the TSDR region. These data show that Mbd2 has a key role in promoting TSDR demethylation, Foxp3 expression and Treg suppressive function. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of MBD2–/– mice, compared to wild type control (all Balb/c background).

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