The protective function of galectin-9 in liver ischemia and reperfusion injury in mice.
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.
Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Departments of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
Hirofumi
H
Hirao
Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Departments of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
Yoichiro
Y
Uchida
Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Departments of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
Kentaro
K
Kadono
Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Hirokazu
H
Tanaka
Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.|GalPharma Co., Ltd., Kagawa, Japan.
Toshiro
T
Niki
Breast Surgery, Kitano Hospital, Osaka, Japan.
Akira
A
Yamauchi
Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Koichiro
K
Hata
Department of Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.
Takeshi
T
Watanabe
Departments of Gastroenterological Surgery and Oncology, Kitano Hospital, Osaka, Japan.
Hiroaki
H
Terajima
Department of Surgery, Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shinji
S
Uemoto
D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D037161:Galectins / Q000235:genetics* / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology; D006706:Homeostasis; D007150:Immunohistochemistry; D007249:Inflammation; D007511:Ischemia / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D037161:Galectins; C508186:galectin 9, mouse