The alkylation of AIM2 by itaconate mediates macrophage PANoptosis during sepsis - PubMed
2 hours ago
- #PANoptosis
- #AIM2
- #Itaconate
- Itaconate, an immunometabolite known for its anti-inflammatory properties, paradoxically drives macrophage cell death and pro-inflammatory responses when accumulated at high levels.
- High concentrations of itaconate covalently alkylate the AIM2 protein at cysteine 113 (C113), stabilizing AIM2 and inducing a conformational change that promotes ASC oligomerization and PANoptosome assembly.
- The AIM2 C113A mutation completely prevents itaconate-induced AIM2 stabilization and PANoptosis, as confirmed through in vitro experiments with lentiviral reconstitution and plasmid-mediated expression.
- In vivo models support the pathogenic role of the itaconate-AIM2 alkylation axis in systemic sepsis, linking it to macrophage depletion and inflammation.
- This study identifies a novel pro-inflammatory mechanism of itaconate through AIM2 modification, offering a potential therapeutic target for severe sepsis.