{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T06:53:33Z","timestamp":1793343213212,"version":"4.5.0"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Introduction<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n Here, we leverage the construction of Cre-lox mouse models to produce mice constitutively lacking either PD-L1 gene expression on endothelial cells (\n ec<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n ) or neutrophils (\n pmn<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n ) 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),\n ec<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n ,\n pmn<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n , and\/or mixed\n flox<\/jats:sup>\n (\n ec<\/jats:italic>\n and\n pmn<\/jats:italic>\n PD-L1\n \u2212\/+<\/jats:sup>\n or PD-L1\n +\/+<\/jats:sup>\n , respectively)-no Cre (Control) mice were subjected to either hemorrhagic (Hem) shock followed 24\u00a0h 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\u00a0h 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\u2019s Blue dye exclusion.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Fourteen-day mortality in the\n ec<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n mice was lower than in the Hem\/CLP Control group, while the mortality rate was increased in the\n pmn<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n vs. Controls. Lung vascular permeability was also markedly decreased in the\n ec<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n Hem\/CLP mice, but no such decline was seen in the lungs of\n pmn<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n 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\n ec<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n vs. Control mice. Alternatively, the lung levels of Angiopoietin 2 and BALF MIP-2 and IL-6 concentrations significantly increased in Hem\/CLP\n pmn<\/jats:italic>\n PD-L1\n \u2212\/\u2212<\/jats:sup>\n animals.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1816915","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T04:29:15Z","timestamp":1780374555000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Endothelial cell, but not neutrophil, programmed cell death receptor-ligand 1 loss has a morbid impact on experimental murine shock\/sepsis-induced lung injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Elizabeth W.","family":"Tindal","sequence":"first","affiliation":[{"name":"Division of Surgical Research, Department of Surgery, Brown University Health-Rhode Island Hospital\/Brown University","place":["Providence, RI, United 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Gutierrez","family":"Garcia","sequence":"additional","affiliation":[{"name":"Division of Surgical Research, Department of Surgery, Brown University Health-Rhode Island Hospital\/Brown University","place":["Providence, RI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theopi","family":"Rados","sequence":"additional","affiliation":[{"name":"Division of Surgical Research, Department of Surgery, Brown University Health-Rhode Island Hospital\/Brown University","place":["Providence, RI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean F.","family":"Monaghan","sequence":"additional","affiliation":[{"name":"Division of Surgical Research, Department of Surgery, Brown University Health-Rhode Island Hospital\/Brown University","place":["Providence, RI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Ayala","sequence":"additional","affiliation":[{"name":"Division of Surgical 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