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Succinate drives gut inflammation by promoting FOXP3 degradation through a molecular switch
Hai Wang1, Danqing Hu2, Yang Cheng1
1Department of Pathology, Center for Human Immunobiology and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Nature Immunology
|June 2, 2025
Summary
Increased succinate promotes inflammatory bowel disease (IBD) by impairing regulatory T (Treg) cells. Succinate reduces FOXP3 expression, leading to gut inflammation and reduced immune suppression in IBD patients.
Area of Science:
- Immunology
- Metabolism
- Gastroenterology
Background:
- Elevated succinate levels are observed in inflammatory bowel disease (IBD).
- The precise role of succinate in IBD pathogenesis is not fully understood.
- Regulatory T (Treg) cells are crucial for immune homeostasis and are often dysfunctional in IBD.
Purpose of the Study:
- To investigate the role of succinate in IBD pathogenesis.
- To elucidate the molecular mechanisms by which succinate affects Treg cell function.
- To identify potential therapeutic targets for IBD based on succinate metabolism.
Main Methods:
- Murine models of colitis were used to study the effects of succinate.
- Expression levels of FOXP3, interleukin-17, and 2-oxoglutarate dehydrogenase complex (OGDHc) were analyzed in Treg cells.
- Genetic deletion of Dlst, an OGDHc component, in Treg cells was performed.
- FOXP3 succinylation and protein degradation pathways were investigated.
- Treg cell function and immune suppressive capacity were assessed.
- Analysis of Treg cells from IBD patients was conducted.
Main Results:
- Succinate promoted colitis in mice by decreasing FOXP3 and increasing interleukin-17 in Treg cells.
- Succinate reduced OGDHc expression, leading to decreased FOXP3 succinylation and subsequent protein degradation.
- Genetic deletion of Dlst in Treg cells resulted in reduced FOXP3, impaired Treg function, and severe gut inflammation.
- Restoring FOXP3 expression rescued the function of Dlst-deficient Treg cells.
- IBD patients exhibited reduced FOXP3 and OGDHc levels in Treg cells, correlating negatively with succinate levels and inflammation severity.
Conclusions:
- Succinate acts as a pathogenic factor in IBD by disrupting Treg cell stability and function.
- Succinate modulates FOXP3 stability through the OGDHc-dependent pathway, creating a molecular switch during inflammation.
- Targeting the succinate-OGDHc-FOXP3 axis may offer a novel therapeutic strategy for IBD.
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