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Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Author

Listed:
  • 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
    University of Cambridge
    University of Cambridge)

  • Emily A. Day

    (Trinity Biomedical Sciences Institute, Trinity College Dublin)

  • Ming Yang

    (University of Cambridge
    University of Cologne)

  • 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
    Cedars–Sinai Medical Center)

  • Lihong Huo

    (Cedars–Sinai Medical Center
    Cedars–Sinai Medical Center)

  • Juliana E. Toller-Kawahisa

    (Trinity Biomedical Sciences Institute, Trinity College Dublin
    Ribeirao Preto Medical School, University of Sao Paulo)

  • 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
    Matterworks)

  • Gabriela Los Santos

    (Cedars–Sinai Medical Center)

  • Mariko Ishimori

    (Cedars–Sinai Medical Center
    University of California Los Angeles)

  • Daniel J. Wallace

    (Cedars–Sinai Medical Center
    University of California Los Angeles)

  • 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
    Cedars–Sinai Medical Center)

  • Christian Frezza

    (University of Cambridge
    University of Cologne)

  • Luke A. J. O’Neill

    (Trinity Biomedical Sciences Institute, Trinity College Dublin)

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.

Suggested Citation

  • 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 & , 2023. "Macrophage fumarate hydratase restrains mtRNA-mediated interferon production," Nature, Nature, vol. 615(7952), pages 490-498, March.
  • Handle: RePEc:nat:nature:v:615:y:2023:i:7952:d:10.1038_s41586-023-05720-6
    DOI: 10.1038/s41586-023-05720-6
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    Cited by:

    1. Marlous Kamp & Jakub Surmacki & Marc Segarra Mondejar & Tim Young & Karolina Chrabaszcz & Fadwa Joud & Vincent Zecchini & Alyson Speed & Christian Frezza & Sarah E. Bohndiek, 2024. "Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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