Post-Stroke Microglia Induce Sirtuin2 Expression to Suppress the Anti-inflammatory Function of Infiltrating Regulatory T Cells

Abstract Ischemic stroke is among the leading causes of death and disability across the globe. Post-stroke neuroinflammation contributes to the pathophysiology of ischemic stroke in the acute phase through damaging neurons in the penumbra region. Infiltrating regulatory T cells (Treg cells) provide neuronal protection in ischemic brains. In the current study using a mouse-transient middle cerebral artery occlusion (MCAO) model, we characterized the changes of sirtuin expression in infiltrating Treg cells in the acute phase of ischemia. We found that Sirt2 was remarkably upregulated in infiltrating Treg cells at day 3 post-MCAO. In vitro inhibition of Sirt2 activity enhanced the expression of immunosuppression-associated molecules including forkhead box P3 (Foxp3) in Treg cells. Using a lentiviral system to express exogenous Sirt2 in Treg cells, we found that Sirt2 weakened the anti-inflammatory effect of Treg cells on pro-inflammatory macrophages. Additionally, post-MCAO microglia increased Sirt2 expression in Treg cells in a cell-to-cell contact manner. We further found that microglia remarkably induced hypoxia-inducible factor 1-alpha (HIF-1 alpha) expression in Treg cells, and inhibition of HIF-1 alpha abolished microglia-induced Sirt2 upregulation. Collectively, we discovered a novel mechanism by which the immunoregulatory activity of infiltrating Treg cells is modulated after ischemia.