Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation

By Vicky Lampropoulou, Alexey A. Sergushichev, M. Bambouskova, S. Nair, E. Vincent, Ekaterina Loginicheva, L. Cervantes-Barragan, Xiucui Ma, S. C. Huang, Takla Griss and 8 more. Cell Metabolism, 2016

1,352 citations recorded by the source corpus.

SUMMARY Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1β-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1−/− mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a49cf803765d61d1911241455399d9bea845b76f

How researchers see this paper

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In Immunology

1. F. Munari
2. R. Sánchez-Rodríguez
3. Tommaso Scolaro
4. A. Viola
5. Alessandra Castegna

In Molecular Biology

1. Ping Gao
2. Huafeng Zhang
3. Linchong Sun

Citations in the corpus

• Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…signal transduction mechanism is as follows: 1) it inhibits SDH and counteracts the proinflammatory signals of succinate (Cordes et al., 2016; Lampropoulou et al., 2016); 2), modifies KEAP1 to activate Nrf2 (Mills et al., 2018); and 3), and induces the ATF3-IκBζ axis, another…”
• The Metabolic Signature of Macrophage Responses (2019, background): “In addition, itaconate may play a role in immunomodulation, suppression of inflammation and tolerance (96).”