Endoplasmic reticulum stress modulates liver inflammatory immune response in the pathogenesis of liver ischemia and reperfusion injury

Jun Liu, Feng Ren, Qiao Cheng, Li Bai, Xiuda Shen, Feng Gao, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Yuan Zhai

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Background: Although endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of organ ischemia-reperfusion injury (IRI), the underlying mechanisms have yet to be fully elucidated. In particular, because tissue proinflammatory immune response is the key mediator of local IRI, how ER stress impacts liver immune cell activation cascade remains to be determined. Methods: In vitro, ER stress in macrophages and hepatocytes were induced by pharmacological agents. Macrophage Toll-like receptor 4 and hepatocyte tumor necrosis factor α responses were studied. In vivo, the induction of ER stress by ischemia-reperfusion and the impact of ER stress amelioration by a small molecule chaperon 4-phenylbutyric acid on liver immune response were studied in a murine partial liver warm ischemia model. Results: ER-stressed macrophages generated a significantly enhanced proinflammatory immune response against Toll-like receptor 4 stimulation, whereas ER-stressed hepatocytes became more susceptible to tumor necrosis factor α-induced cell death. Ischemia-reperfusion resulted in up-regulations of spliced X-box binding protein 1 and activating transcription factor 6 levels in affected livers. Mice pretreated with 4-phenylbutyric acid were protected from liver IRI, in parallel with diminished local proinflammatory gene induction program. Conclusions: Our study documents a potential immune regulatory role of ER stress in the mechanism of liver IRI and provides a rationale for targeting stress response as a new therapeutic means to ameliorate tissue inflammation in organ transplant recipients.

Original languageEnglish (US)
Pages (from-to)211-217
Number of pages7
JournalTransplantation
Volume94
Issue number3
DOIs
StatePublished - Aug 15 2012

Keywords

  • ER stress
  • Inflammation
  • Liver ischemia
  • TLR-4

ASJC Scopus subject areas

  • Transplantation

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