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.… Click to show full 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 ACOD1 in human and mouse macrophages or monocytes. Genetic deletion of CDK2 or ACOD1 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. Description CDK2-dependent up-regulation of ACOD1 in macrophages and monocytes mediates lethal infection in an itaconate-independent manner. Demystifying aconitate decarboxylase 1 Aconitate decarboxylase 1 (ACOD1) produces itaconate, which has known anti-inflammatory functions. However, it is unclear whether ACOD1 has a role in sepsis apart from itaconate production. Using cecal ligation and puncture to generate polymicrobial sepsis in mice, Wu et al. found that ACOD1 was up-regulated in myeloid cells by cyclin-dependent kinase 2 (CDK2) during sepsis, leading to activation of immune pathways and sustained proinflammatory signaling. Furthermore, genetic depletion of either CDK2 or ACOD1, or the administration of the CDK inhibitor dinaciclib, protected mice from cytokine storm and death after cecal ligation and puncture. These findings highlight the proinflammatory role of ACOD1 in sepsis and suggest CDK inhibition as a potential treatment.
               
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