Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

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

Nomenclatural Changes in Ipomopsis Congesta (Polemoniaceae)

Volume: 27Start Page: 111End Page: 11

SESSILE-FLOWERED SPECIES IN THE NAVARRETIA LEUCOCEPHALA GROUP (POLEMONIACEAE)

Volume: 42Start Page: 34End Page: 3

Acanthogilia, a new genus of Polemoniaceae from Baja California, Mexico

Volume: 44Start Page: 111End Page: 12

Transfer of some species from Gilia to Allophyllum and Tintinabulum, and the effects of the transfer on the generic definition of Gilia (Polemoniaceae)

Volume: 84Start Page: 368End Page: 38

A NEW GILIA (POLEMONIACEAE) FROM LIMESTONE OUTCROPS IN THE SOUTHERN SIERRA NEVADA OF CALIFORNIA

Volume: 45Start Page: 137End Page: 14

A HETEROSTYLOUS GILIA (POLEMONIACEAE) FROM CENTRAL NEVADA

Volume: 41Start Page: 120End Page: 12