T-Cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner

Yoichiro Uchida, Bibo Ke, Maria Cecilia S. Freitas, Hideo Yagita, Hisaya Akiba, Ronald W. Busuttil, Nader Najafian, Jerzy W. Kupiecweglinski

Research output: Contribution to journalArticlepeer-review

102 Scopus citations


Background & Aims T-cell immunoglobulin mucin (TIM) genes are expressed by T cells and regulate host immunity and tolerance. CD4+ T cells mediate innate immunity-dominated liver ischemia-reperfusion injury (IRI) by unknown mechanisms. TIM-1 is involved in liver IRI, which is activated in part by the Toll-like receptor (TLR)4; we investigated the role of TIM-3 and TLR4 in IRI. Methods Using an antibody against TIM-3 (antiTIM-3), we studied TIM-3 signaling in mice following partial warm liver ischemia and reperfusion. Results Mice given antiTIM-3 had more liver damage than controls. Histological studies revealed that antiTIM-3 increased hepatocellular damage and local neutrophil infiltration, facilitated local accumulation of T cells and macrophages, and promoted liver cell apoptosis. Intrahepatic neutrophil activity; induction of proinflammatory cytokines and chemokines; and expression of cleaved caspase-3, nuclear factor-κB, and TLR4 all increased in mice given antiTIM-3. Administration of antiTIM-3 followed by antigalectin-9 (Gal-9 is a TIM-3 ligand) increased production of interferon-γ by concanavalin A (ConA)-stimulated spleen T cells and expression of tumor necrosis factor-α and interleukin-6 in ConA-stimulated macrophages co-cultured with T cells. AntiTIM-3 did not affect liver IRI in TLR4-deficient mice. Conclusion TIM-3 blockade exacerbated local inflammation and liver damage, indicating the importance of TIM-3Gal-9 signaling in maintaining hepatic homeostasis. TIM-3TLR4 cross-regulation determined the severity of liver IRI in TLR4-dependent manner; these findings provide important information about the modulation of innate vs adaptive responses in patients that received liver transplants. Negative co-stimulation signaling by hepatic T-cells might be developed to minimize innate immunity-mediated liver tissue damage.

Original languageEnglish (US)
Pages (from-to)2195-2206
Number of pages12
Issue number6
StatePublished - Dec 2010


  • Ischemia Reperfusion Injury
  • Liver
  • T-cell Immunoglobulin Mucin
  • Toll-like Receptor 4

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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