ACOD1 regulates microglial arginine metabolism and inflammatory responses

Eleftheria Karadima; Canelif Yılmaz; Anupam Sinha; Georgia Fodelianaki; Sofia Dimothyra; Nikolaos Nirakis; Sofia Traikov; Nicola Zamboni; Ben Wielockx; Panayotis Verginis; Mirko Peitzsch; T Chavakis; Vasileia Ismini Alexaki

doi:10.3389/fimmu.2026.1731962

ImmunologyFrontiers in ImmunologyMar 16, 2026

Peer-reviewed journal article

ACOD1 regulates microglial arginine metabolism and inflammatory responses

Eleftheria Karadima iD, Canelif Yılmaz iD, Anupam Sinha, Georgia Fodelianaki, Sofia Dimothyra iD, Nikolaos Nirakis iD, Sofia Traikov iD, Nicola Zamboni iD, Ben Wielockx iD, Panayotis Verginis iD, Mirko Peitzsch iD, T Chavakis, Vasileia Ismini Alexaki iD

Abstract

Itaconate is produced by inflammatory macrophages and promotes a negative feedback on inflammation. It is synthesized by aconitate decarboxylase 1 (ACOD1) from cis- aconitate, a metabolite of the tricarboxylic acid cycle. Here, we studied the role of ACOD1 in the inflammatory response of microglia, the resident macrophage-like cells of the brain. Similar to macrophages, ACOD1 deficient microglia displayed a stronger inflammatory response to lipopolysaccharide (LPS) compared to their wild type counterparts. The proinflammatory effects of ACOD1 deficiency were associated with reprogramed arginine metabolism entailing enhanced argininosuccinate synthesis at the expense of polyamine synthesis, in a manner that was dependent on ACLY. These findings provide new insights in the immunometabolic role of ACOD1 in inflammatory microglia.

PDF DOI