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 De Los Santos, Mariko Ishimori, Daniel J. Wallace, Swamy VenuturupalliEfterpi Nikitopoulou, Norma Frizzell, Cecilia Johansson, Alexander von Kriegsheim, Michael P. Murphy, Caroline Jefferies, Christian Frezza, Luke A.J. O'Neill

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Metabolic rewiring underlies the effector functions of macrophages 1–3, 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.

Original languageEnglish
Pages (from-to)490-498
JournalNature
Volume615
Early online date8 Mar 2023
DOIs
Publication statusE-pub ahead of print - 8 Mar 2023

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