Aconitate decarboxylase 1 is a mediator of polymicrobial sepsis

Abstract

Sepsis is a challenging clinical syndrome caused by a dysregulated host response to infection. Here, we identified an unexpected proseptic activity of aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages. Previous studies have suggested that ACOD1, also known as immune-responsive gene 1, is an immunometabolic regulator that favors itaconate production to inhibit bacterial lipopolysaccharide-induced innate immunity. We used next-generation sequencing of lipopolysaccharide-activated THP1 cells to demonstrate that ACOD1 accumulation confers a robust proinflammation response by activating a cytokine storm, predominantly through the tumor necrosis factor signaling pathway. We further revealed that the phosphorylation of cyclin-dependent kinase 2 (CDK2) on threonine-160 mediates the activation of mitogen-activated protein kinase 8 through receptor for activated C kinase 1, leading to JUN-dependent transcription of <i>ACOD1</i> in human and mouse macrophages or monocytes. Genetic deletion of <i>CDK2</i> or <i>ACOD1</i> in myeloid cells, or the administration of the CDK inhibitor dinaciclib, protected mice against polymicrobial sepsis and was associated with improved survival and decreased cytokine storm. The expression of the CDK2-ACOD1 axis also correlated with severity of illness in a cohort of 40 patients with bacterial sepsis. Thus, our findings provide evidence for a previously unrecognized function of ACOD1 in innate immunity and suggest it as a potential therapeutic target for the treatment of sepsis.