2. Academic Validation
  3. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

  • Nature. 2023 Mar 8. doi: 10.1038/s41586-023-05720-6.
Alexander Hooftman # 1,  Christian G Peace # 2,  Dylan G Ryan # 3 4 5,  Emily A Day 2,  Ming Yang 6 7,  Anne F McGettrick 2,  Maureen Yin 2,  Erica N Montano 8 9,  Lihong Huo 8 9,  Juliana E Toller-Kawahisa 2 10,  Vincent Zecchini 6,  Tristram A J Ryan 2,  Alfonso Bolado-Carrancio 11,  Alva M Casey 12,  Hiran A Prag 12,  Ana S H Costa 6 13,  Gabriela De Los Santos 8,  Mariko Ishimori 8 14,  Daniel J Wallace 8 14,  Swamy Venuturupalli 8,  Efterpi Nikitopoulou 6,  Norma Frizzell 15,  Cecilia Johansson 16,  Alexander Von Kriegsheim 11,  Michael P Murphy 12,  Caroline Jefferies 8 9,  Christian Frezza 6 7,  Luke A J O'Neill 17
Affiliations

Affiliations

  • 1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. [email protected].
  • 2 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
  • 3 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. [email protected].
  • 4 MRC Cancer Unit, University of Cambridge, Cambridge, UK. [email protected].
  • 5 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK. [email protected].
  • 6 MRC Cancer Unit, University of Cambridge, Cambridge, UK.
  • 7 CECAD Research Centre, Faculty of Medicine, University of Cologne, Cologne, Germany.
  • 8 Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 9 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 10 Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo, Brazil.
  • 11 Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh, UK.
  • 12 MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
  • 13 Matterworks, Somerville, MA, USA.
  • 14 David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • 15 School of Medicine, University of South Carolina, Columbia, SC, USA.
  • 16 National Heart and Lung Institute, Imperial College London, London, UK.
  • 17 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. [email protected].
  • # Contributed equally.
PMID: 36890227 DOI: 10.1038/s41586-023-05720-6
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.

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