Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor

Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor. [Image: see text

The resurgence of German capital in Europe: EU integration and the restructuring of Atlantic networks of interlocking directorates after 1991

European integration is interpreted in this paper as the route by which (West) Germany, profiting from close ties with the English-speaking West, was able to restore its full sovereignty and economic pre-eminence in Europe. Yet in shaping the actual integration process, it was France which played the key role. Most of the landmark steps towards the current EU were French proposals to pre-empt Anglophone-German collusion; creating European structures in which a resurgence of Germany (politically and economically) was made subject to permanent negotiation. German unification in 1991 removed the one reason why successive governments of the Federal Republic had gone along with this. Paradoxically, sovereign Germany today finds itself bound by the dense networks of consultation and decision-making which make the EU unique in the field of regional integration. The paper shows that between 1992 and 2005, German capital has moved to the centre of the network of corporate interlocks in the North Atlantic area. This helps to explain why in the post-1991, post-Soviet era of neoliberal, finance-driven globalisation, Germany is increasingly 'speaking for Europe', as its corporations have become nodal points in the communication structures through which the responses to the challenges facing the EU and the West at large are being shaped