Macrophage fumarate hydratase restrains mtRNA-mediated interferon production.
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2023-03-08Access:
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Hooftman A, Peace CG, Ryan DG, Day EA, Yang M, McGettrick AF, Yin M, Montano EN, Huo L, Toller-Kawahisa JE, Zecchini V, Ryan TAJ, Bolado-Carrancio A, Casey AM, Prag HA, Costa ASH, De Los Santos G, Ishimori M, Wallace DJ, Venuturupalli S, Nikitopoulou E, Frizzell N, Johansson C, Von Kriegsheim A, Murphy MP, Jefferies C, Frezza C, O'Neill LAJ., Macrophage fumarate hydratase restrains mtRNA-mediated interferon production., Nature, 2023, 32Download Item:
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Abstract:
Metabolic rewiring underlies the effector functions of macrophages, 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.
Sponsor
Grant Number
National Institutes of Health (NIH)
R01NS1268
National Institutes of Health (NIH)
R01AI164504
Wellcome Trust
Multiuser Equipment Grant, 208402/Z/17/Z
European Research Council (ERC)
Metabinnate 834370
Medical Research Council (MRC)
MRC_MC_UU_12022/6
Medical Research Council (MRC)
MR/V000659/1
Medical Research Council (MRC)
MC_ UU_00028/4
Wellcome Trust
Investigator award 220257/Z/20/Z
European Research Council (ERC)
Consolidator ERC819920
Science Foundation Ireland (SFI)
20/SPP/3685
Author's Homepage:
http://people.tcd.ie/laoneillhttp://people.tcd.ie/mcgettra
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PUBLISHED
Author: Mc Gettrick-Dillon, Anne; O'Neill, Luke
Publisher:
Springer NatureType of material:
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Nature;Availability:
Full text availableKeywords:
Macrophages, Fumarate hydrataseSubject (TCD):
Immunology, Inflammation & InfectionDOI:
http://dx.doi.org/10.1038/s41586-023-05720-6ISSN:
0028-0836Licences: