Dataset Information

The protective function of galectin-9 in liver ischemia and reperfusion injury in mice.

ABSTRACT: Galectin-9 (Gal-9) has gained attention as a multifaceted player in adaptive and innate immunity. To elucidate the role of Gal-9, we used a mouse model of partial liver ischemia/reperfusion injury (IRI) with wild type (WT) and Gal-9 knockout (KO) mice as well as a recombinant galectin-9 (reGal-9) protein. We found that the expression of Gal-9 was enhanced endogenously in the liver especially by hepatocytes and Kupffer cells during warm IRI for a mouse liver, which causes massive destruction of liver tissue. Gal-9 was released into the extracellular space in the liver and the highest levels in the plasma at 1 hour after reperfusion. The present study elucidates a novel role of Gal-9 signaling in mouse liver IRI, by using Gal-9-deficient mice and a stable form of reGal-9 protein. In the circumstance of Gal-9 absence, liver damage due to ischemia/reperfusion (IR) exacerbated the severity as compared with WT. On the other hand, exogenously administered reGal-9 significantly ameliorated hepatocellular damage. It decreased the local infiltration of the inflammatory cells such as T cells, neutrophils, and macrophages, and it reduced the expression of proinflammatory cytokines/chemokines; then, it strongly suppressed the apoptosis of the liver cells. Interestingly, severe liver damage due to IR in Gal-9 KO mice was improved by the administration of reGal-9. In conclusion, Gal-9 engagement ameliorated local inflammation and liver damage induced by IR, and the present study suggests a significant role of Gal-9 in the maintenance of hepatic homeostasis. In conclusion, targeting Gal-9 represents a novel approach to protect from inflammation such as liver IRI. Exogenous Gal-9 treatment will be a new therapeutic strategy against innate immunity-dominated liver tissue damage.

SUBMITTER: Hirao H

PROVIDER: S-EPMC4744675 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The protective function of galectin-9 in liver ischemia and reperfusion injury in mice.

Hirao Hirofumi H Uchida Yoichiro Y Kadono Kentaro K Tanaka Hirokazu H Niki Toshiro T Yamauchi Akira A Hata Koichiro K Watanabe Takeshi T Terajima Hiroaki H Uemoto Shinji S

Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 20150701 7

Galectin-9 (Gal-9) has gained attention as a multifaceted player in adaptive and innate immunity. To elucidate the role of Gal-9, we used a mouse model of partial liver ischemia/reperfusion injury (IRI) with wild type (WT) and Gal-9 knockout (KO) mice as well as a recombinant galectin-9 (reGal-9) protein. We found that the expression of Gal-9 was enhanced endogenously in the liver especially by hepatocytes and Kupffer cells during warm IRI for a mouse liver, which causes massive destruction of l ...[more]

PMID: 25931247

Similar Datasets

Project description:Ischemic stroke is one of the most common causes of mortality worldwide and is a primary cause of disability and mortality in adults. There is an unmet need for drugs that can effectively treat ischemic stroke. Hence, the present study explored the neuroprotective effects of andrographolide (Andro) in a mouse model of bilateral common carotid artery occlusion, and systematically evaluated the potential mechanisms underlying its effects. The effects of Andro on mouse brain tissue following cerebral ischemia‑reperfusion injury (CIRI) were evaluated by histopathological (H&E and Nissl) and immunofluorescence [glial fibrillary acidic protein (GFAP) and neuronal nuclei (NeuN)] staining. A traditional Chinese medicine‑based network pharmacology method was performed to establish and analyze compound‑target‑disease and function‑pathway networks in order to elucidate the possible mechanisms responsible for the protective role of Andrographis paniculata in CIRI. In addition, western blot analysis and RT‑qPCR was performed to evaluate the expression and activation of signaling proteins predicted to be involved in this mechanism. The amelioration of histopathological alterations was observed in mice pre‑treated with Andro. Immunofluorescence staining revealed that Andro decreased the expression of GFAP and increased the expression of NeuN, and significantly decreased the levels of pro‑inflammatory cytokines (IL‑1β, IL‑6 and TNF‑α). Network pharmacology analysis revealed that neuroinflammatory response and apoptosis were associated with the effects of Andrographis paniculata on CIRI. Western blot analysis revealed that the mice pre‑treated with Andro exhibited an upregulated protein expression of tropomyosin receptor kinase B (TrkB), p‑PI3K and p‑Akt, as well as a decrease in the expression of GFAP and an increase in the expression of NeuN. In addition, the data of RT‑qPCR indicated that the mice pre‑treated with Andro exhibited a significantly decreased expression of encoding IL‑1β mRNA, IL‑6 mRNA and TNF‑α mRNA in the brain compared to the untreated mice following CIRI. On the whole, the findings of the present study suggest that pre‑treatment with Andro exerts a protective effect against CIRI, which may be partly related to its potential to reduce neuroinflammatory response and apoptosis in patients with stroke.

Project description:Background & aimsBy binding to T cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation.MethodsWe used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20 h at 4°C in UW solution) and syngeneic orthotopic liver transplantation (OLT).ResultsOrthotopic liver transplants in WT or TIM-3Tg→TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg→WT groups were susceptible to IRI. TIM-3 induction in circulating CD4+ T cells of the recipient: (1) depressed T-bet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD-1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we documented for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in vivo and in vitro. Moreover, exogenous recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells.ConclusionsHarnessing TIM-3/Gal-9 signalling at the T cell-hepatocyte interface facilitates homeostasis in IR-stressed orthotopic liver transplants. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR-resistance. Negative regulation by recipient TIM-3+CD4+ cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients.

Dataset Information

The protective function of galectin-9 in liver ischemia and reperfusion injury in mice.

Publications

The protective function of galectin-9 in liver ischemia and reperfusion injury in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets