PD-L1 (Programmed Death Ligand 1) Protects Against Experimental Intracerebral Hemorrhage-Induced Brain Injury

Abstract

Background and purpose: Intracerebral hemorrhage (ICH) is a neurologically destructive stroke, for which no valid treatment is available. This preclinical study examined the therapeutic effect of PD-L1 (programmed death ligand 1), a B7 family member and a ligand for both PD-1 (programmed death 1) and B7-1 (CD80), in a murine ICH model.

Methods: ICH was induced by injecting autologous blood into 252 male C57BL/6 and Rag1^-/- mice. One hour later, ICH mice were randomly assigned to receive an intraperitoneal injection of vehicle, PD-L1, or anti-PD-L1 antibody. Neurological function was assessed along with brain edema, brain infiltration of immune cells, blood-brain barrier integrity, neuron death, and mTOR (mammalian target of rapamycin) pathway products.

Results: PD-L1 significantly attenuated neurological deficits, reduced brain edema, and decreased hemorrhage volume in ICH mice. PD-L1 specifically downsized the number of brain-infiltrating CD4⁺ T cells and the percentages of Th1 and Th17 cells but increased the percentages of Th2 and regulatory T cells. In the PD-L1-treated group, we observed an amelioration of the inflammatory milieu, decreased cell death, and enhanced blood-brain barrier integrity. PD-L1 also inhibited the mTOR pathway. The administration of anti-PD-L1 antibody produced the opposite effects to those of PD-L1 in ICH mice.

Conclusions: PD-L1 provided protection from the damaging consequences of ICH.

Keywords: PD-L1; cerebral hemorrhage; hematoma; inflammation; stroke.