A novel role for programmed cell death receptor ligand 2 in sepsis-induced hepatic dysfunction

Anne Lise Rossi, Marilyn Le, Chun Shiang Chung, Yaping Chen, Eleanor A. Fallon, Andres Matoso, Shumin Xu, Tristen T. Chun, Craig P. Erickson, Alfred Ayala

Research output: Contribution to journalArticle

Abstract

The liver is an organ that, when dysfunctional in a septic patient, is strongly associated with morbidity and mortality. Understanding the pathophysiology of liver failure during sepsis may lead to improved diagnostics and potential therapeutic targets. Historically, programmed cell death receptor (PD) ligand 1 (PD-L1) has been considered the primary ligand for its checkpoint molecule counterpart, PD-1, with PD-L2 rarely in the immunopathological spotlight. PD-1 and PD-L1 contribute to liver dysfunction in a murine cecal ligation and puncture (CLP) model of sepsis, but virtually nothing is known about PD-L2's role in sepsis. Therefore, our central hypothesis was that sepsis-induced changes in hepatic PD-L2 expression contributed to worsened liver function and, subsequently, more pronounced morbidity and mortality. We found that although PD-L1 gene deficiency attenuated the hepatic dysfunction seen in wild-type mice after CLP, the loss of PD-L2 appeared to actually worsen indices of liver function along with a trend toward higher liver tissue vascular permeability. Conversely, some protective effects of PD-L2 gene deletion were noted, such as reduced liver/peritoneal bacterial load and reduced IL-6, IL-10, and macrophage inflammatory protein 2 levels following CLP. These diverse actions, as well as the unique expression pattern of PD-L2, may explain why no overt survival advantage could be witnessed in the septic PD-L2-/- mice. Taken together, these data suggest that although PD-L2 has some selective effects on the hepatic response seen in the septic mouse, these factors are not sufficient to alter septic mortality in this adult murine model. NEW & NOTEWORTHY Our study shows not only that ligands of the checkpoint protein PD-1 respond inversely to a stressor such as septic challenge (PD-L2 declines, whereas PD-L1 rises) but also that aspects of liver dysfunction increase in septic mice lacking the PD-L2 gene. Furthermore, these differences in PD-L2 gene-deficient animals culminated in the abrogation of the survival advantage seen in the septic PD-L1-knockout mice, suggesting that PD-L2 may have roles beyond a simple immune tolerogen.

Original languageEnglish (US)
Pages (from-to)G106-G114
JournalAmerican journal of physiology. Gastrointestinal and liver physiology
Volume316
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Death Domain Receptors
Sepsis
Cell Death
Ligands
Liver
Punctures
Ligation
Mortality
Liver Diseases
Chemokine CXCL2
Genes
Morbidity
Bacterial Load
Liver Failure
Gene Deletion
Capillary Permeability
Knockout Mice
Interleukin-10
Interleukin-6
Survival

Keywords

  • inflammation
  • posttranslational modification
  • programmed cell death receptor ligand 1
  • programmed cell death receptor-1
  • sepsis

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

A novel role for programmed cell death receptor ligand 2 in sepsis-induced hepatic dysfunction. / Rossi, Anne Lise; Le, Marilyn; Chung, Chun Shiang; Chen, Yaping; Fallon, Eleanor A.; Matoso, Andres; Xu, Shumin; Chun, Tristen T.; Erickson, Craig P.; Ayala, Alfred.

In: American journal of physiology. Gastrointestinal and liver physiology, Vol. 316, No. 1, 01.01.2019, p. G106-G114.

Research output: Contribution to journalArticle

Rossi, Anne Lise ; Le, Marilyn ; Chung, Chun Shiang ; Chen, Yaping ; Fallon, Eleanor A. ; Matoso, Andres ; Xu, Shumin ; Chun, Tristen T. ; Erickson, Craig P. ; Ayala, Alfred. / A novel role for programmed cell death receptor ligand 2 in sepsis-induced hepatic dysfunction. In: American journal of physiology. Gastrointestinal and liver physiology. 2019 ; Vol. 316, No. 1. pp. G106-G114.
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AU - Matoso, Andres

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