Glycogen Synthase Kinase 3 beta in liver ischemia reperfusion injury

糖原合酶激酶3β在肝脏缺血再灌注损伤中的作用

• 批准号: 10721921
• 负责人: YUAN ZHAI
• 金额: $ 33.98万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721921
• 关键词: 5' -AMP-activated protein kinase; Acceleration; Acute; Address; Affect; Anti-Inflammatory Agents; Autophagocytosis; Bone Marrow; Cell Death Induction; Cell Respiration; Cell physiology; Cells; Chronic; Clinical; Complication; Disease; Down-Regulation; Excision; Functional disorder; Generations; Genes; Glycogen Synthase Kinases; Graft Rejection; Hepatocellular Damage; Heterogeneity; Homeostasis; Immune; Immune response; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Ischemia; Knockout Mice; Kupffer Cells; Liver; Liver neoplasms; Macrophage; Macrophage Activation; Mediating; Metabolic; Modeling; Molecular; Mus; Myelogenous; Neutrophil Infiltration; Operative Surgical Procedures; Outcome; Oxygen; Pathogenesis; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Peripheral; Phenotype; Phosphotransferases; Play; Population; Population Heterogeneity; Primary carcinoma of the liver cells; Receptor Protein-Tyrosine Kinases; Recovery; Regulation; Reperfusion Injury; Resolution; Risk Factors; Role; Signal Transduction; Stress; Testing; Therapeutic; Time; Tissues; Transplantation; Warm Ischemia; clinically relevant; design; experimental study; flexibility; glycogen synthase kinase 3 beta; immune activation; immune cell infiltrate; in vivo; inhibitor; insight; ischemic injury; liver inflammation; liver injury; liver ischemia; liver transplantation; new therapeutic target; novel; novel therapeutic intervention; nutrient deprivation; preservation; programs; receptor; repair function; repaired; response; restraint; tissue injury; tumor

Project Summary Ischemia reperfusion injury (IRI) is a major complication after liver surgery. In liver transplantation, it is a major risk factor for both acute and chronic graft rejection and restrains the use of marginal donors. Liver inflammatory immune response drives the pathogenesis of IRI. Despite the progress in studies of cellular and molecular mechanisms of the response, questions regarding to the potential distinctive roles of tissue resident vs. infiltration macrophages (iMФs), and the resolution of liver IRI remain to be defined. Glycogen synthase kinase 3β (Gsk3β) is a unique signaling kinase that it differentially regulates pro- and anti-inflammatory gene programs in MФs upon innate stimulations. It has been shown in a murine liver partial warm ischemia model that both Gsk3 inhibitors in WT hosts and myeloid Gsk3β deficiency protect livers from IRI via an AMPK- IL-10-dependent mechanism. The clinical relevance of AMPK in liver ischemia has been documented recently in hepatic tumor resection. Preliminary experiments of this proposal have found that Gsk3β also regulates the resolution of liver IRI. In fact, Gsk3β regulates liver inflammatory immune activation and resolution by targeting distinctive populations of liver MФs. KCs depletion diminished the liver protective phenotype in myeloid Gsk3β KO mice against IR. However, the recovery of liver IRI remain accelerated in these KC-depleted KO hosts, indicating that Gsk3β regulates iMФs in resolving tissue inflammation. Current proposal will dissect mechanisms of Gsk3β regulation of these two types of MФs at different stages of liver IRI. IR-induced liver inflammatory immune activation is characterized by infiltration and activation of MФs from peripheral (iMՓs), as well as necroptotic depletion and pro-inflammatory conversion of tissue resident KCs. In liver inflammation resolution, MФs repair hepatocellular damage and clear infiltrated neutrophils via Tyro3-Axl-MerTK (TAM) receptor tyrosine kinase (RTK)-mediated efferocytosis. Macrophage necroptosis and efferocytosis potently regulate their activation and differentiation. Gsk3β promotes stress-induced cell death and regulates TAM expressions in MФs. The proposal will test the hypothesis that Gsk3β regulates KC necroptosis via AMPK and pro-inflammatory immune activation via Mer RTK; and Gsk3β inhibition/inactivation facilitates iMФ conversion from pro-inflammatory to reparative type by enhancing Axl-mediated efferocytosis and immune regulatory signaling. Two specific aims are designed to address how Gsk3β regulates KC inflammatory activation, and iMФ reprogramming/functions, in the activation and resolution stages of liver IRI, respectively. Results of these experiments shall offer fresh new insight into immune regulatory functions of Gsk3β in MФs in both the activation and resolution of liver inflammation and injuries and provide rationales for novel therapeutic strategies to restore liver homeostasis in patients.

项目摘要 缺血再灌注损伤(IRI)是肝脏手术后的主要并发症。在肝移植中，它是 这是急性和慢性移植物排斥反应的主要风险因素，限制了边缘供者的使用。肝 炎症免疫反应推动了IRI的发病。尽管在细胞和细胞的研究方面取得了进展 反应的分子机制，关于组织驻留的潜在独特作用的问题 与浸润巨噬细胞(ImФS)的比较，以及肝脏IRI的分辨率仍有待确定。 糖原合成酶激酶3β(GSK3β)是一种独特的信号转导通路，它能差异化地调节细胞外信号转导途径。 以及MФS在天生刺激下的抗炎基因程序。它已经在小鼠的肝脏中显示出来。 WT宿主GSK_3抑制剂和髓系GSK_3β缺陷共同保护肝脏的部分热缺血模型 通过AMPK-IL-10依赖机制从IRI。AMPK在肝缺血中的临床意义 近年来在肝肿瘤切除术中得到了报道。对这一建议的初步试验发现， GSK3β也调节肝脏IRI的分辨率。事实上，GSK3β调节肝脏炎症免疫激活 和针对特定人群的肝脏MФS。KCS耗竭减弱了对肝脏的保护作用 髓系Gsk3βKO小鼠抵抗IR的表型。然而，肝脏IRI的恢复仍然加速。 这些KC缺失的KO宿主，表明GSK3β调节IMФS在解决组织炎症中的作用。当前 本研究拟对GSK3β在肝脏缺血再灌注损伤不同阶段对这两种MФ的调节机制进行剖析。 IR诱导的肝炎性免疫激活以M-ФS的浸润和激活为特征 来自外周的(ImՓS)，以及坏死性枯竭和促炎转化的组织常驻 KCS。在肝脏炎症消退中，MФS修复肝细胞损伤，并通过 酪氨酸激酶受体()介导的胞吐作用。巨噬细胞坏死性下垂和 泡泡吞噬作用有效地调节它们的激活和分化。Gsk3β促进应激诱导的细胞死亡 和调节在MФS中的表达。该提案将检验GSK3β调控KC的假设 AMPK途径的坏死性下垂和Mer RTK、Gsk3β途径的促炎免疫激活 抑制/失活通过以下途径促进IMФ从促炎型向修复型转化 增强Axl介导的胞吐作用和免疫调节信号。 设计了两个特定的目标来解决GSK3β如何调节KC炎症激活，以及IMФ 重新编程/功能，分别在肝脏IRI的激活和分解阶段。这些措施的结果 实验将为GSK3β在MФ中的免疫调节功能提供新的新视角 激活和化解肝脏炎症和损伤，为新的治疗方法提供理论依据 恢复患者肝脏动态平衡的策略。

项目成果

Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK.

• DOI: 10.1172/jci.insight.151819
• 发表时间: 2023-01-10
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Zhang, Hanwen;Ni, Ming;Wang, Han;Zhang, Jing;Jin, Dan;Busuttil, Ronald W.;Kupiec-Weglinski, Jerzy W.;Li, Wei;Wang, Xuehao;Zhai, Yuan
• 通讯作者: Zhai, Yuan