Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Alexander Hooftman (), Christian G. Peace, Dylan G. Ryan (), Emily A. Day, Ming Yang, Anne F. McGettrick, Maureen Yin, Erica N. Montano, Lihong Huo, Juliana E. Toller-Kawahisa, Vincent Zecchini, Tristram A. J. Ryan, Alfonso Bolado-Carrancio, Alva M. Casey, Hiran A. Prag, Ana S. H. Costa, Gabriela Los Santos, Mariko Ishimori, Daniel J. Wallace, Swamy Venuturupalli, Efterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander Kriegsheim, Michael P. Murphy, Caroline Jefferies, Christian Frezza and Luke A. J. O’Neill ()
Additional contact information
Alexander Hooftman: Trinity Biomedical Sciences Institute, Trinity College Dublin
Christian G. Peace: Trinity Biomedical Sciences Institute, Trinity College Dublin
Dylan G. Ryan: Trinity Biomedical Sciences Institute, Trinity College Dublin
Emily A. Day: Trinity Biomedical Sciences Institute, Trinity College Dublin
Ming Yang: University of Cambridge
Anne F. McGettrick: Trinity Biomedical Sciences Institute, Trinity College Dublin
Maureen Yin: Trinity Biomedical Sciences Institute, Trinity College Dublin
Erica N. Montano: Cedars–Sinai Medical Center
Lihong Huo: Cedars–Sinai Medical Center
Juliana E. Toller-Kawahisa: Trinity Biomedical Sciences Institute, Trinity College Dublin
Vincent Zecchini: University of Cambridge
Tristram A. J. Ryan: Trinity Biomedical Sciences Institute, Trinity College Dublin
Alfonso Bolado-Carrancio: University of Edinburgh
Alva M. Casey: University of Cambridge
Hiran A. Prag: University of Cambridge
Ana S. H. Costa: University of Cambridge
Gabriela Los Santos: Cedars–Sinai Medical Center
Mariko Ishimori: Cedars–Sinai Medical Center
Daniel J. Wallace: Cedars–Sinai Medical Center
Swamy Venuturupalli: Cedars–Sinai Medical Center
Efterpi Nikitopoulou: University of Cambridge
Norma Frizzell: University of South Carolina
Cecilia Johansson: National Heart and Lung Institute, Imperial College London
Alexander Kriegsheim: University of Edinburgh
Michael P. Murphy: University of Cambridge
Caroline Jefferies: Cedars–Sinai Medical Center
Christian Frezza: University of Cambridge
Luke A. J. O’Neill: Trinity Biomedical Sciences Institute, Trinity College Dublin

Nature, 2023, vol. 615, issue 7952, 490-498

Abstract: 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: 2023
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DOI: 10.1038/s41586-023-05720-6

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