Abstract WMP68: Loss Of Programmed Cell Death Ligand 1 And 2 Reduces Total Infarct Volume In Male Mice Following Experimental Stroke
The programmed cell death 1 receptor (PD-1) is an immunoglobulin superfamily member whose expression is induced in activated T cells, B cells, natural killer cells and monocytes. Binding of PD-1 to either of its two known ligands, programmed cell death ligand 1 and 2 (PD-L1 and PD-L2), induces inhibitory signals that regulate peripheral T cell tolerance and immune homeostasis. We have shown increased PD-1 expression in brain macrophages and glia as well as increased PD-L1 and PD-L2 expression in peripheral and brain B cells in mice after experimental stroke. Furthermore, we have observed increased infarct volume in PD-1 deficient mice, thus potentially implicating the PD-1/PD-L co-inhibitory pathway in post-stroke CNS inflammation. Using PD-L1 and PD-L2deficient mice, we determined if PD-L1 or PD-L2 was also important in modulating stroke infarct volume. Young adult male wild-type (WT; n=11) and PD-L1 (n=9) and PD-L2 (n=12) knockout (KO) mice underwent 60 min of middle cerebral artery occlusion via intraluminal filament. Laser-Doppler flowmetry was used to monitor cortical perfusion. All mice were euthanized and brains collected at 96 h of reperfusion. Total infarct volume (% corrected contralateral hemisphere) was determined by image analysis of coronal brain slices stained with 2,3,5-triphenyltetrazolium chloride (TTC). Relative laser Doppler flowmetry changes (% baseline) during and after middle cerebral artery occlusion were equivalent among groups. Compared to male WT mice (WT vs. KO), genetic deletion of either PD-L1 (51+3% vs. 20+5%; p<0.001) or PD-L2 (51+3% vs. 35+4%; p=0.007) reduced total infarct volume. We also observed that total infarct volume was smaller in PD-L1 vs. PD-L2 KO mice (20+5% vs. 35+4%; p=0.017). Our findings along with our previous work in PD-1 deficient mice suggest that ligands other than PD-L1 or PD-L2 might be involved with PD-1 signaling in ischemic brain and that PD-L1 and PD-L2 might have other functions independent of PD-1 binding affecting infarct volumes. Future studies will evaluate the roles of PD-1, PD-L1, and PD-L2 in regulatory immune cell subsets that affect ischemic brain outcomes. This study was supported by National Institutes of Health grant NS075887.
- © 2012 by American Heart Association, Inc.