ACOD1 regulates microglial arginine metabolism and inflammatory responses

Itaconate is produced by inflammatory macrophages and negatively feedbacks 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. Similarly to macrophages, ACOD1 deficient microglia displayed a stronger inflammatory response to lipopolysaccharide (LPS) compared to their wild type counterparts. ACOD1 deficiency reprogramed arginine metabolism by enhancing argininosuccinate synthesis in the expense of polyamine synthesis in an ACLY-dependent manner. These findings provide new insights in the immunometabolic role of ACOD1 in inflammatory microglia. LPS versus PBS (in-vitro): Primary murine microglia were treated with 100 ng/ml LPS or carrier (PBS) for 4 h. Transcriptional changes were analyzed by bulk RNAseq. LPS versus PBS (in-vivo): C57BL/6J mice were treated interaperitoneally with 3 mg/kg LPS or PBS and 4 h later whole brain microglia (CD45intermCD11b+Ly6G-) were FACS sorted and analyzed by bulk RNAseq. Acod1-/- versus Wt: Acod1-/- and Wt mice were treated interaperitoneally with 3 mg/kg LPS or PBS and 16 h later whole brain microglia (CD45intermCD11b+Ly6G-) were FACS sorted and analyzed by bulk RNAseq.