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INTRODUCTION: Stroke is a leading cause of death and long-term disability worldwide. Acute ischemia results in a profound inflammatory response that is counterproductive to short- and long-term recovery. Programmed Death Protein 1 (PD-1) is an immune checkpoint that has been shown to be upregulated after acute cerebral injury, and—upon binding its ligand PD-L1—negatively regulates immune cells to limit the inflammatory response. METHODS: C57BL/6J mice underwent middle cerebral artery occlusion (MCAO) and were randomized into three arms: (1)sham surgery, (2)MCAO control, and (3)MCAO+PD-L1. Survival, brain water content, and volumetric MRI analysis of cerebral edema were measured. Brains were analyzed by flow cytometry to quantify PD-1 expression on infiltrating immune cells. Peripheral blood was harvested for single-cell RNA-sequencing. Blood from stroke patients was collected, and the frequency of PD-1+ monocytes was correlated to clinical outcomes. RESULTS: PD-L1 significantly decreased brain edema as measured by brain water content (p = 0.0277) and high-resolution MRI (p < 0.0001), and improved overall survival (p = 0.0022). PD-1+ monocytes are upregulated in the ischemic hemisphere, and appear to be critical mediators of edema. PD-L1 treatment decreased PD-1+ monocyte infiltration , while global PD-1 (PD-1-/-) and myeloid-specific knockout of PD-1 (PD-1f/fLysMcre) abrogated the treatment effect on edema. Single-cell RNA sequencing and differential expression analysis of peripheral monocytes revealed downregulation of multiple pro-inflammatory pathways in the treated mice versus the controls. Human correlative studies confirmed that PD-1+ monocytes were present in the peripheral blood of MCA stroke patients, and the frequency of this cell population correlated with post-stroke cerebral edema. CONCLUSIONS: Our results support PD-L1 as a novel therapeutic strategy for neuroinflammation and cerebral edema after acute ischemic stroke.
Kim et al. (Fri,) studied this question.