Aberrant fumarate metabolism links interferon release in diffuse systemic sclerosis.

Steadman, Thomas; O'Reilly, Steven

Abstract

Background
Systemic Sclerosis (SSc) is an idiopathic rheumatic inflammatory disease that is characterised by inflammation and skin fibrosis. Type I interferon is significantly elevated in the disease.
Objective
The objective of this study is to determine the role of the TCA cycle metabolite fumarate in SSc.
Methods
CD14 + cells were isolated from 12 SSc patients and healthy controls. Fumarate hydratase and Interferon dependant genes were quantified by qPCR. In vitro inhibition of STING using a small molecule STING inhibitor and enforced mitophagy was induced in vitro and IFN-β release was quantified. VDAC1 inhibitor was used to determine the role of mt DNA release in IFN-β induction. In whole skin biopsies fumarate and succinate was quantified.
Results
Fumarate Hydratase is significantly reduced in SSc monocytes. Type I interferon is also elevated in monocytes from SSc donors compared to controls. The mitochondrial-specific stress marker GDF-15 was significantly elevated in SSc monocytes. Blockade of the cGAS-STING pathway chemically reduced interferon-β release and induced mitophagy also retarded release of the cytokine in response to LPS stimulation. Inhibition of VDAC1 mitigated IFN-β, as did the depletion of mitochondria in cells. Furthermore, the itaconate derivative 4-octyl itaconate reduced IFN-β induction in SSc monocytes, that was downstream of mitochondrial nucleic acid release. Fumarate, but not succinate was elevated in whole skin biopsies.
Conclusion
Fumarate metabolism links interferon release in SSc and may underlie the aberrant expression of interferon in SSc via cytosolic DNA released from mitochondria.

Citation

Steadman, T., & O'Reilly, S. (2025). Aberrant fumarate metabolism links interferon release in diffuse systemic sclerosis. Journal of Dermatological Science, 117(2), 30-35. https://doi.org/10.1016/j.jdermsci.2025.01.002

• Journal Article Type: Article
• Acceptance Date: Jan 6, 2025
• Online Publication Date: Jan 8, 2025
• Publication Date: 2025-02
• Deposit Date: Feb 18, 2025
• Journal: Journal of Dermatological Science
• Print ISSN: 0923-1811
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 117
• Issue: 2
• Pages: 30-35
• DOI: https://doi.org/10.1016/j.jdermsci.2025.01.002
• Keywords: Interferon, Fumarate hydratase, Fibrosis, DNA, STING, Systemic sclerosis, CGAS
• Public URL: https://durham-repository.worktribe.com/output/3474611