A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction
Abstract Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, the co-inhibitory molecule programmed death-ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previ...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2016-10-01
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| Series: | Molecular Medicine |
| Online Access: | http://link.springer.com/article/10.2119/molmed.2016.00150 |
| _version_ | 1819065275062943744 |
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| author | Youping Wu Chun-Shiang Chung Yaping Chen Sean Farrell Monaghan Sima Patel Xin Huang Daithi Seamus Heffernan Alfred Ayala |
| author_facet | Youping Wu Chun-Shiang Chung Yaping Chen Sean Farrell Monaghan Sima Patel Xin Huang Daithi Seamus Heffernan Alfred Ayala |
| author_sort | Youping Wu |
| collection | DOAJ |
| description | Abstract Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, the co-inhibitory molecule programmed death-ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previous studies showed that PD-L1 gene deficiency reduced sepsis-induced intestinal injury morphologically. However, it is not known how PD-L1 expression impacts intestinal barrier dysfunction during sepsis. Here we tested the hypothesis that PD-L1 expressed on intestinal epithelial cells (IECs) has a role in sepsis-induced intestinal barrier dysfunction. To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability and tissue cytokine levels were assessed. Subsequently, septic or nonseptic colonic samples (assigned by pathology report) were immunohistochemically stained for PD-L1 in a blinded fashion. Finally, human Caco2 cells were used for in vitro studies. The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly upregulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability and tissue levels of IL-6, TNF-α and MCP-1, and prevented ileal tight junction protein loss compared with WT after sepsis. Comparatively, while Caco2 cell monolayers also responded to inflammatory cytokine stimulation with elevated PD-L1 expression, increased monolayer permeability and altered/decreased monolayer tight junction protein morphology/expression, these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction. |
| first_indexed | 2024-12-21T15:43:52Z |
| format | Article |
| id | doaj.art-684fc801ef264cd68dd4020429623f9d |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-21T15:43:52Z |
| publishDate | 2016-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-684fc801ef264cd68dd4020429623f9d2022-12-21T18:58:26ZengBMCMolecular Medicine1076-15511528-36582016-10-0122183084010.2119/molmed.2016.00150A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal DysfunctionYouping Wu0Chun-Shiang Chung1Yaping Chen2Sean Farrell Monaghan3Sima Patel4Xin Huang5Daithi Seamus Heffernan6Alfred Ayala7Department of Anesthesiology, Changhai Hospital, Second Military Medical UniversityDepartment of Surgery, Division of Surgical Research, Alpert School of Medicine at Brown University/Aldrich 227, Rhode Island HospitalDepartment of Surgery, Division of Surgical Research, Alpert School of Medicine at Brown University/Aldrich 227, Rhode Island HospitalDepartment of Surgery, Division of Surgical Research, Alpert School of Medicine at Brown University/Aldrich 227, Rhode Island HospitalDepartment of Biochemistry and Molecular Biology, Brown UniversityDepartment of Surgery, Division of Surgical Research, Alpert School of Medicine at Brown University/Aldrich 227, Rhode Island HospitalDepartment of Surgery, Division of Surgical Research, Alpert School of Medicine at Brown University/Aldrich 227, Rhode Island HospitalDepartment of Surgery, Division of Surgical Research, Alpert School of Medicine at Brown University/Aldrich 227, Rhode Island HospitalAbstract Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, the co-inhibitory molecule programmed death-ligand1 (PD-L1) has been shown to be involved in the regulation of intestinal immune tolerance and/or inflammation. Our previous studies showed that PD-L1 gene deficiency reduced sepsis-induced intestinal injury morphologically. However, it is not known how PD-L1 expression impacts intestinal barrier dysfunction during sepsis. Here we tested the hypothesis that PD-L1 expressed on intestinal epithelial cells (IECs) has a role in sepsis-induced intestinal barrier dysfunction. To address this, C57BL/6 or PD-L1 gene knockout mice were subjected to experimental sepsis and PD-L1 expression, intestinal permeability and tissue cytokine levels were assessed. Subsequently, septic or nonseptic colonic samples (assigned by pathology report) were immunohistochemically stained for PD-L1 in a blinded fashion. Finally, human Caco2 cells were used for in vitro studies. The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly upregulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability and tissue levels of IL-6, TNF-α and MCP-1, and prevented ileal tight junction protein loss compared with WT after sepsis. Comparatively, while Caco2 cell monolayers also responded to inflammatory cytokine stimulation with elevated PD-L1 expression, increased monolayer permeability and altered/decreased monolayer tight junction protein morphology/expression, these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction.http://link.springer.com/article/10.2119/molmed.2016.00150 |
| spellingShingle | Youping Wu Chun-Shiang Chung Yaping Chen Sean Farrell Monaghan Sima Patel Xin Huang Daithi Seamus Heffernan Alfred Ayala A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction Molecular Medicine |
| title | A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction |
| title_full | A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction |
| title_fullStr | A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction |
| title_full_unstemmed | A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction |
| title_short | A Novel Role for Programmed Cell Death Receptor Ligand-1 in Sepsis-Induced Intestinal Dysfunction |
| title_sort | novel role for programmed cell death receptor ligand 1 in sepsis induced intestinal dysfunction |
| url | http://link.springer.com/article/10.2119/molmed.2016.00150 |
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