Aconitate decarboxylase 1 suppresses cerebral ischemia-reperfusion injury in mice.

Immunometabolic changes have been shown to be a key factor in determining the immune cell response in disease models. The immunometabolite, itaconate, is produced by aconitate decarboxylase 1 (Acod1) and has been shown to inhibit inflammatory signaling in macrophages. In this study, we explore the role of Acod1 and itaconate in cerebral ischemia/reperfusion injury. We assessed the effect of global Acod1 knockout (Acod1KO, loss of endogenous itaconate) in a transient ischemia/reperfusion occlusion stroke model. Mice received a transient 90-min middle cerebral artery occlusion followed with 24-h of reperfusion. Stroke lesion volume was measured by MRI analysis and brain tissues were collected for mRNA gene expression analysis. Acod1KO mice showed significant increases in lesion volume compared to control mice, however no differences in pro-inflammatory mRNA levels were observed. Cell specific knockout of Acod1 in myeloid cells (LysM-Cre), microglia cells (CX3CR1, Cre-ERT2) and Endothelial cells (Cdh5(PAC), Cre-ERT2) did not reproduce lesion volume changes seen in global Acod1KO, indicating that circulating myeloid cells, resident microglia and endothelial cell populations are not the primary contributors to the observed phenotype. These effects however do not appear to be driven by changes in inflammatory gene regulation. These data suggests that endogenous Acod1 is protective in cerebral ischemia/reperfusion injury. • Global knockout of aconitate decarboxylase 1 (Acod1KO) leads to increased lesion volumes following transient ischemic stroke. • The increases in lesion volume observed in Acod1KO are not caused by changes in inflammatory gene expression. • Cell specific knockout of Acod1 from circulating myeloid cells, microglia, and endothelial cells does not phenocopy Acod1KO. • This indicates Acod1 has an important role in ischemic stroke damage and its effects may involve other resident brain cells. [ABSTRACT FROM AUTHOR]