Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Metabolic rewiring underlies the effector functions of macrophages1-3, but the mechanisms involved remain incompletely defined. Here, using unbiased metabolomics and stable isotope-assisted tracing, we show that an inflammatory aspartate-argininosuccinate shunt is induced following lipopolysaccharide stimulation. The shunt, supported by increased argininosuccinate synthase (ASS1) expression, also leads to increased cytosolic fumarate levels and fumarate-mediated protein succination. Pharmacological inhibition and genetic ablation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) further increases intracellular fumarate levels. Mitochondrial respiration is also suppressed and mitochondrial membrane potential increased. RNA sequencing and proteomics analyses demonstrate that there are strong inflammatory effects resulting from FH inhibition. Notably, acute FH inhibition suppresses interleukin-10 expression, which leads to increased tumour necrosis factor secretion, an effect recapitulated by fumarate esters. Moreover, FH inhibition, but not fumarate esters, increases interferon-β production through mechanisms that are driven by mitochondrial RNA (mtRNA) release and activation of the RNA sensors TLR7, RIG-I and MDA5. This effect is recapitulated endogenously when FH is suppressed following prolonged lipopolysaccharide stimulation. Furthermore, cells from patients with systemic lupus erythematosus also exhibit FH suppression, which indicates a potential pathogenic role for this process in human disease. We therefore identify a protective role for FH in maintaining appropriate macrophage cytokine and interferon responses.
Date Issued
2023-03
Date Acceptance
2023-01-10
Citation
Nature, 2023, 615 (7952), pp.490-498
ISSN
0028-0836
Publisher
Nature Research
Start Page
490
End Page
498
Journal / Book Title
Nature
Volume
615
Issue
7952
Copyright Statement
© The Author(s), under exclusive licence to Springer Nature Limited 2023. This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1038/s41586-023-05720-6
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/36890227
PII: 10.1038/s41586-023-05720-6
Subjects
Argininosuccinate Synthase
Argininosuccinic Acid
Aspartic Acid
Cell Respiration
Cytosol
Fumarate Hydratase
Fumarates
Humans
Interferon-beta
Lipopolysaccharides
Lupus Erythematosus, Systemic
Macrophages
Membrane Potential, Mitochondrial
Metabolomics
Mitochondria
RNA, Mitochondrial
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2023-03-08