Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental animal model of sepsis.

Abstract

PD-L1 is a ligand for PD-1 and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. Here we show PD-L1 expression negatively correlates with rates of apoptosis in human neutrophils harvested from patients with sepsis. Using co-immunoprecipitation assays on control neutrophils challenged with IFN-γ and LPS, we show PD-L1 complexes with the p85 subunit of PI3-K to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared to wild-type animals, PD-L1-deficient animals presented lower plasma levels of plasma TNF-α and IL-6 and higher IL-10 following CLP, and reduced seven-day mortality in CLP PD-L1 knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI-3K-dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.