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Kupffer cells potentiate the risk for liver sinusoidal endothelial cell injury in sepsis through programmed cell death receptor‐1 ligation
Author(s) -
Hutchins Noelle Ariane,
Wang Fei,
Chung ChunShiang,
Ayala Alfred
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.379.8
Subject(s) - sepsis , kupffer cell , liver injury , immune system , apoptosis , medicine , receptor , ligation , immunology , programmed cell death , septic shock , cancer research , biology , biochemistry
Endothelial cell (EC) dysfunction contributes to multiple organ injury—the cause of fatality seen in critically ill patients. Studies suggest that liver sinusoidal ECs (LSECs) maintain immune tolerance by directly ligating programmed‐death receptor‐1 (PD‐1) on leukocytes by their cell surface expression of PD‐ligand‐1 (PD‐L1). Reports indicate that LSECs express PD‐L1, but its role in the septic liver remains unknown. Thus, we hypothesized that increased PD‐1 + leukocyte & PD‐L1 + LSEC interactions in sepsis, would lead to greater EC injury. We initially noted that increased EC permeability from septic livers induced by cecal ligation and puncture (CLP) in wild‐type (WT) mice decreased in CLP PD‐L1−/− mice. Isolated LSECs (CD146 + CD45 − cells) had an increase of PD‐L1 in CLP WT mice. We also found that LSECs from CLP PD‐L1−/− mice exhibit less apoptosis compared to CLP WT mice. Septic LSECs had lower expression of angiogenic marker VEGF‐R2, less proliferation, & a 2x‐fold decrease in number vs. Shams; all of which were rescued in CLP PD‐L1−/− mice. Finally, there was a rise in PD‐1 + Kupffer cells (KCs), which are needed for septic LSEC PD‐L1 expression. These data suggests that increased interactions between PD‐1 + KCs & PD‐L1 + LSECs results in injury during sepsis, yet suppresses tolerance, angiogenesis & proliferation—essential for normal EC function. Supported by: NIH—F31DK083873 (N.H.) & NIH—R01GM053209 (A.A.)