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Differential Effects of Endothelial Cell- as opposed to Neutrophil-Lineage Restricted PD-L1 Gene Expression on
Elizabeth W Tindal1, Chun-Shiang Chung1, Yaping Chen1
1Brown University Health-Rhode Island Hospital.
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/ 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 (ecPD-L1-/-) or neutrophils (pmnPD-L1-/-), respectively, to test the hypothesis that endothelial cell as opposed to neutrophil deficiency PD-L1 differentially contributes to shock/ sepsis induced lung injury/ death.
Methods:
Adult male C57BL/6 (WT), ecPD-L1-/-, pmnPD-L1-/- and/or mixed flox-no cre (Control) mice were subjected to either hemorrhagic (Hem) shock followed 24 hrs by cecal ligation & puncture (CLP) (Hem/CLP) or sham Hem and sham CLP (Sham). Survival studies were done. A separate set of animals were taken at 24 hrs post-procedure for peripheral blood, broncho-alveolar lavage fluid (BALF), lung tissues were harvested, processed/ stained for flow cytometry, cytokine/ chemokine/ 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:
14-day mortality in the ecPD-L1-/- mice was lower than in the Hem/CLP Control group, while the mortality rate was increased in the pmnPD-L1-/- vs. Controls. Lung vascular permeability was also markedly decreased in the ecPD-L1-/- Hem/CLP mice but no such decline was seen in the lungs of pmnPD-L1-/- mice. While Hem/CLP increased the lung tissue, BALF and blood levels of several cytokine/ chemokine/angiopoietin levels, the concentrations of lung tissue, BALF MCP-1 and blood BUN markedly declined in the ecPD-L1-/- vs. Control mice. Alternatively, the lung levels of Angiopoietin-2 and BALF MIP-2 and IL-6 concentrations significantly increased in Hem/CLP pmnPD-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.
