title: A Novel Role for Programmed Cell Death Receptor Ligand-1 (PD-L1) in Sepsis-Induced Intestinal Dysfunction.
abstract: Studies imply that intestinal barrier dysfunction is a key contributor to morbid events associated with sepsis. Recently, 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 isn't 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, tissue cytokine levels were assessed. Subsequently, septic or non-septic patient colonic samples (assigned by pathology report) were immunohistochemically stained for PD-L1 I a blinded fashion. Finally, human Caco2 cells were used forin vitrostudies. The results demonstrated that PD-L1 was constitutively expressed and sepsis significantly up-regulates PD-L1 in IECs from C57BL/6 mice. Concurrently, we observed an increased PD-L1 expression in colon tissue samples from septic patients. PD-L1 gene deficiency reduced ileal permeability, tissue levels of IL-6, TNF-α and MCP-1, and prevented ileal tight junction protein loss compared to WT after sepsis. Comparatively, while Caco2 cell monolayers responded to inflammatory cytokine stimulation also with elevated PD-L1 expression, increased monolayer permeability and altering/decreasing monolayer tight junction protein morphology/expression; these changes were reversed by PD-L1 blocking antibody. Together these data indicate that ligation of ICE PD-L1 plays a novel role in mediating the pathophysiology of sepsis-induced intestinal barrier dysfunction.
authors: Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, PR China.
authors: Youping
authors: Y
authors: Wu
authors: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
authors: Chun-Shiang
authors: CS
authors: Chung
authors: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
authors: Yaping
authors: Y
authors: Chen
authors: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
authors: Sean Farrell
authors: SF
authors: Monaghan
authors: Department of Biochemistry and Molecular Biology, Brown University, Providence, RI 02912, USA.
authors: Sima
authors: S
authors: Patel
authors: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
authors: Xin
authors: X
authors: Huang
authors: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
authors: Daithi Seamus
authors: DS
authors: Heffernan
authors: Department of Surgery, Division of Surgical Research, the Alpert School of Medicine at Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
authors: Alfred
authors: A
authors: Ayala
keywords: Caco2 cells; cytokines; intestinal permeability; mouse; tight junction proteins