The Role And Mechanism Of Programmed Death Ligand 1 In Intracerebral Hemorrhage Damage

Background and Purpose intracerebral hemorrhage(ICH)is a particularly severe type of cerebrovascular diseases with high mortality and disability.The incidence of ICH is 24.6 per 100,000 people per year at present,and that figure could double by2050.No specific drug or surgical treatment has been applied to ICH beyond symptomatic and supportive therapy.The early phase injury of ICH is mainly caused by the mass effect of hematoma;however,the most severe neurological injury comes out 2-3 days post ICH.Once ICH happens,resident microglia is activated and releases proinflammatory mediators,which recruit peripheral leukocytes into central nervous system.T lymphocytes are the predominant kind of leukocytes that infiltrate the brain.The programmed death 1(PD-1),which is a transmembrane glycoprotein of the CD28/ CTLA-4 immunoglobulin superfamily,has two differentially expressed ligands,PD-L1 and PD-L2.The PD-1/ PD-L1 pathway contributes directly to T-cell depletion.The aim of this study is to investigate the potential effect of PD-L1 and its monoclonal antibody in ICH and elucidate the underlying mechanism.Methods ICH was induced by injecting 30?l autologous blood into male C57BL/6J mice.One hour after surgery,ICH mice were randomly assigned to receive an intraperitoneal injection of vehicle,PD-L1,or anti-PD-L1 antibody.Neurological function was assessed the day and days after ICH.Three days after ICH induction,different parts of brain were weighed to obtain their wet weight and dry weight to evaluate the extent of brain edema.Brain were harvested for flow cytometry to analyze infiltration of immune cells,for real-time polymerase chain reaction(RT-PCR)to evaluate the cytokine in brain tissue,for western blot to assess blood-brain barrier integrity and explore the pathway of PD-L1 in ICH.Results PD-L1 significantly attenuated neurological deficits and reduced brain edema,hemorrhage volume in ICH mice.It also reduced the number of brain-infiltrating CD4+ T cells,the percentage of Th1 and Th17 cells,and increased the percentage of Th2 and regulatory T cells(Treg).In the PD-L1-treated group,we observed ameliorated inflammatory milieu and enhanced blood-brain barrier integrity.PD-L1 also inhibited the mTOR pathway.Administration of the anti-PD-L1 antibody showedthe opposite effects of PD-L1 in ICH mice.Conclusions PD-L1 protected mice from the consequences of experimental ICH,mainly by modulating CD4+ T cell population via the inhibition of the mTOR pathway.