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This study examines how the loss of PD-L1 in endothelial cells versus neutrophils affects lung injury and survival during sepsis.

June 6, 2026Open Access

Endothelial cell, but not neutrophil, programmed cell death receptor-ligand 1 loss has a morbid impact on experimental murine shock/sepsis-induced lung injury

Key Points

This study examines how the loss of PD-L1 in endothelial cells versus neutrophils affects lung injury and survival during sepsis.
Utilized Cre-lox mouse models to create ec PD-L1 -/- and pmn PD-L1 -/- mice.
Subjected mice to hemorrhagic shock followed by cecal ligation and puncture or sham procedures.
Analyzed survival rates, cytokine levels, and lung vascular permeability using flow cytometry and ELISAs.
Mortality in ec PD-L1 -/- mice was lower compared to controls after shock/sepsis.
Lung vascular permeability decreased in ec PD-L1 -/- mice, contrasting with no change in pmn PD-L1 -/- mice.
Cytokine levels were altered significantly, with certain markers declining in ec PD-L1 -/- mice and increasing in pmn PD-L1 -/- mice.

Abstract

Introduction Our laboratory and others have shown that programmed cell death receptor-ligand 1 (PD-L1) contributes to the development of shock/sepsis-induced morbidity and mortality, but its role appears to vary across organ/cell type. Objective Here, we leverage the construction of Cre-lox mouse models to produce mice constitutively lacking either PD-L1 gene expression on endothelial cells ( ec PD-L1 −/− ) or neutrophils ( pmn PD-L1 −/− ) to test the hypothesis that endothelial cell as opposed to neutrophil deficiency of PD-L1 differentially contributes to shock/sepsis-induced lung injury/death. Methods: Adult male C57BL/6 (breeder background strain), ec PD-L1 −/− , pmn PD-L1 −/− , and/or mixed flox ( ec and pmn PD-L1 −/+ or PD-L1 +/+ , respectively)-no Cre (Control) mice were subjected to either hemorrhagic (Hem) shock followed 24 h by cecal ligation and puncture (CLP) (Hem/CLP) or sham Hem and sham CLP (Sham). Survival studies were performed, and a separate set of animals were taken at 24 h post-procedure for peripheral blood, bronchoalveolar lavage fluid (BALF), and lung tissue collection. Samples were processed and stained for analysis by flow cytometry, cytokine, chemokine, and angiopoietin ELISAs and indices of organ injury assays. A subset of animals was also examined for changes in lung permeability using Evan’s Blue dye exclusion. Results Fourteen-day mortality in the ec PD-L1 −/− mice was lower than in the Hem/CLP Control group, while the mortality rate was increased in the pmn PD-L1 −/− vs. Controls. Lung vascular permeability was also markedly decreased in the ec PD-L1 −/− Hem/CLP mice, but no such decline was seen in the lungs of pmn PD-L1 −/− mice. While Hem/CLP increased the lung tissue, BALF, and blood levels of several cytokine, chemokine, and angiopoietin levels, the concentrations of lung tissue and BALF MCP-1 and blood urea nitrogen markedly declined in the ec PD-L1 −/− vs. Control mice. Alternatively, the lung levels of Angiopoietin 2 and BALF MIP-2 and IL-6 concentrations significantly increased in Hem/CLP pmn PD-L1 −/− animals. Conclusions Taken together, these results support the hypothesis we have previously proffered, that expression of PD-L1 on endothelial cells has a morbid impact. However, surprisingly, we have also uncovered a potential immune protective role of PD-L1 expression on neutrophils.

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