{"title":"Inhibition of crosstalk between iNKT cells and macrophages mitigates ischemia-reperfusion injury in steatotic livers","authors":"Yu Kuroda , Yoshiya Ito , Nobuyuki Nishizawa , Mina Tanabe , Atsushi Yamashita , Kanako Hosono , Mariko Kamata , Masashi Satoh , Yusuke Kumamoto , Naoki Hiki , Hideki Amano","doi":"10.1016/j.yexcr.2025.114728","DOIUrl":null,"url":null,"abstract":"<div><div>Liver ischemia-reperfusion (IR) injury is a substantial form of damage that occurs during liver transplantation and resection surgeries. Steatotic livers are particularly susceptible to IR injury, but few strategies to effectively alleviate this issue in steatotic livers exist. Invariant natural killer T (iNKT) cells regulate IR injury in healthy livers as well as liver repair by interacting with macrophages. In this study, we explored the role of iNKT cell-macrophage crosstalk in IR injury in steatotic livers. High-fat diet (HFD)-fed macrophage-specific CD1d conditional knockout (<em>Cd1d</em><sup><em>△mac</em></sup>) and Cd1d<sup>flox</sup> control (Cont) mice were subjected to liver IR. HFD-fed <em>CD1d</em><sup><em>△mac</em></sup> mice showed mitigation of IR-induced liver damages with reduction of hepatic necrosis and inflammation along with promotion of liver repair. Flow cytometric analysis revealed that HFD-fed <em>Cd1d</em><sup><em>△mac</em></sup> mice showed increased hepatic reparative macrophages and interleukin (IL)-13-positive iNKT cells but decreased pro-inflammatory macrophages with IL-1β. IL-13 administration to HFD-fed Cont mice attenuated IR injury and accelerated liver recovery, which was associated with accumulation of hepatic macrophages skewed to a reparative phenotype. IL-13 promoted reparative macrophage polarization in bone marrow (BM)-derived <em>Cd1d</em>-deficient macrophages in vitro. Blockade of IL-13 in HFD-fed <em>Cd1d</em><sup><em>△mac</em></sup> mice aggravated IR injury. Overall, inhibiting iNKT cell-macrophage crosstalk attenuates steatotic liver IR injury and facilitates liver repair via IL-13-mediated reparative macrophage polarization. These findings provide new insights into therapeutic strategies to regulate the vulnerability of the steatotic liver to IR injury.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"451 2","pages":"Article 114728"},"PeriodicalIF":3.5000,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental cell research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014482725003283","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Liver ischemia-reperfusion (IR) injury is a substantial form of damage that occurs during liver transplantation and resection surgeries. Steatotic livers are particularly susceptible to IR injury, but few strategies to effectively alleviate this issue in steatotic livers exist. Invariant natural killer T (iNKT) cells regulate IR injury in healthy livers as well as liver repair by interacting with macrophages. In this study, we explored the role of iNKT cell-macrophage crosstalk in IR injury in steatotic livers. High-fat diet (HFD)-fed macrophage-specific CD1d conditional knockout (Cd1d△mac) and Cd1dflox control (Cont) mice were subjected to liver IR. HFD-fed CD1d△mac mice showed mitigation of IR-induced liver damages with reduction of hepatic necrosis and inflammation along with promotion of liver repair. Flow cytometric analysis revealed that HFD-fed Cd1d△mac mice showed increased hepatic reparative macrophages and interleukin (IL)-13-positive iNKT cells but decreased pro-inflammatory macrophages with IL-1β. IL-13 administration to HFD-fed Cont mice attenuated IR injury and accelerated liver recovery, which was associated with accumulation of hepatic macrophages skewed to a reparative phenotype. IL-13 promoted reparative macrophage polarization in bone marrow (BM)-derived Cd1d-deficient macrophages in vitro. Blockade of IL-13 in HFD-fed Cd1d△mac mice aggravated IR injury. Overall, inhibiting iNKT cell-macrophage crosstalk attenuates steatotic liver IR injury and facilitates liver repair via IL-13-mediated reparative macrophage polarization. These findings provide new insights into therapeutic strategies to regulate the vulnerability of the steatotic liver to IR injury.
期刊介绍:
Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.