ACOD1 regulates microglial arginine metabolism and inflammatory responses

TL;DR

ACOD1 helps control inflammation in microglia by regulating arginine metabolism and acetyl-CoA levels.

Contribution

This study reveals a novel role for ACOD1 in modulating microglial inflammation through arginine and acetyl-CoA metabolism.

Findings

ACOD1 deficiency in microglia leads to stronger inflammatory responses compared to wild type.

ACOD1 deficiency enhances argininosuccinate synthesis while reducing polyamine biosynthesis.

ACLY inhibition reverses the metabolic effects caused by ACOD1 deficiency.

Abstract

Itaconate is produced by inflammatory macrophages and promotes negative feedback on inflammation. It is synthesized by aconitate decarboxylase 1 (ACOD1) from cis-aconitate, a metabolite of the tricarboxylic acid cycle. Here, we focused on the role of ACOD1 in the immunometabolic reprograming of inflammatory microglia. 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 enhanced ATP citrate lyase (ACLY) activity and elevated acetyl-CoA amounts, and reprogramed arginine metabolism entailing enhanced argininosuccinate synthesis at the expense of polyamine biosynthesis. These effects of ACOD1 deficiency on arginine metabolism were reversed by ACLY inhibition. These findings provide new insights in the immunometabolic role of ACOD1.

Figures