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Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.

Accepted version
Peer-reviewed

Type

Article

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Authors

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.

Description

Keywords

Humans, Argininosuccinate Synthase, Argininosuccinic Acid, Aspartic Acid, Cell Respiration, Cytosol, Fumarate Hydratase, Fumarates, Interferon-beta, Lipopolysaccharides, Lupus Erythematosus, Systemic, Macrophages, Membrane Potential, Mitochondrial, Metabolomics, Mitochondria, RNA, Mitochondrial

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

615

Publisher

Springer Science and Business Media LLC

Rights

Publisher's own licence
Sponsorship
Medical Research Council (MC_UU_12022/6)
European Research Council (819920)
Wellcome Trust (220257/Z/20/Z)
Medical Research Council (MC_UU_00015/3)