title: Disruption of TIM-4 in dendritic cell ameliorates hepatic warm IR injury through the induction of regulatory T cells.
abstract: Hepatic ischaemia reperfusion (IR) injury results from the infiltration of multiple immune cells especially dendritic cells (DC). T-cell immunoglobulin-domain and mucin-domain 4 (TIM-4) is a type I cell-surface glycoprotein which is extensively expressed on antigen presenting cells (APC) like DC and macrophages. TIM-4 has been demonstrated to be implicated in mucosal allergy, skin allograft rejection and tumour-immune tolerance. However, the role of TIM-4 expressed on DC in hepatic IR injury remains largely unknown. In the present study, we aimed to investigate whether and how DC expressed TIM-4 was involved in hepatic IR injury. With segmental hepatic warm ischaemia mice models, we demonstrated that promoted DC infiltration and increased TIM-4 expression were induced by hepatic IR. Blockade of TIM-4 by anti-TIM-4 mAb (0.35mg/mouse) markedly ameliorated hepatic injury and reduced inflammatory cytokine secretion. Furthermore, in a DC:CD4+ T cell co-culture system, blockade of TIM-4 on DC significantly inhibited T helper-2 cell differentiation and facilitated induced CD4+ CD25+ Foxp3+ T regulatory cell (iTreg) expansion. Interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (Stat 6) signalling was shown to be impeded by TIM-4 blockade and involved in iTreg generation. Additionally, adoptive transfer of iTreg produced by TIM-4 blockade into hepatic IR mice models remarkably attenuated liver injury. We conclude that TIM-4 on DC play a critical role in hepatic IR injury and may be an efficient target for the prevention of liver or other organ IR injury.
authors.affiliation: Department of Anesthesiology, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Tumor Center, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Tumor Center, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, The First Hospital of Jilin University, Changchun 130021, Jilin, PR China. Electronic address: huanqiuliujilin@126.com.
authors.forename: Huanqiu
authors.initials: H
authors.lastname: Liu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008099:Liver; D008111:Liver Function Tests; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D013696:Temperature; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008565:Membrane Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C500399:TIM-4 protein, mouse; D015847:Interleukin-4
keywords: Dendritic cell; Hepatic ischaemia reperfusion; Induced T regulatory cell; Interleukin 4; Signal transducer and activator of transcription 6; T-cell immunoglobulin-domain and mucin-domain 4