Succinate is a danger signal that induces IL-1β via HIF-1α

By G. Tannahill, A. Curtis, Juraj Adamik, E. Palsson-McDermott, A. F. Mcgettrick, G. Goel, C. Frezza, N. Bernard, B. Kelly, N. Foley and 22 more. Nature, 2013

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Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the ‘GABA (γ-aminobutyric acid) shunt’ pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.

Subfields: Immunology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/21c3f3d8a01f66c1d2d13f06d7223d3f523029ac

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Citations in the corpus

THE INTERLEUKIN-1 FAMILY: BACK TO THE FUTURE (2013, positive): “Accumulation of succinate in classically Immunity 39, December 12, 2013 ª2013 Elsevier Inc. 1005 activatedM1macrophages (Tannahill et al., 2013) stabilizes hypoxia-inducible factor a (HIF-1a), which in turn induces IL-1b.”
Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation (2018, background): “, succinate, α-ketoglutarate, citrate, and itaconate) that regulates LPS macrophage activation [119].”
A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury. (2016, background): “…probably in conjunction with elevated ROS (Guzy et al., 2008), can stabilize the hypoxia-inducible factors (HIFs) by inhibiting their HIF-α prolyl hydroxylases-mediated degradation, thus leading to activation of a pseudohypoxic response (Selak et al., 2005; Tannahill et al., 2013) (Figure 2).”
Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response through a HIF-1α/Glycolysis-Dependent Axis (2020, background): “HIF-1a is a strong inducer of glycolysis and IL-1b transcription (Tannahill et al., 2013).”
Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity (2016, background): “Citric acid cycle metabolites (e.g., fumarate and succinate) have previously been reported to regulate HIF1a stabilization by inhibiting hydroxylation and therefore stabilizing HIF1a (Koi- vunen et al., 2007; Tannahill et al., 2013).”