Kupffer Cell Necroptosis and Homeostatic Function in Liver Immune Responses against Ischemia Reperfusion Injury

库普弗细胞坏死性凋亡和肝脏缺血再灌注损伤免疫反应中的稳态功能

• 批准号: 9167747
• 负责人: YUAN ZHAI
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9167747
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Cell Death; Cell physiology; Cells; Clinic; Clinical; Data; Dichloromethylene Diphosphonate; Dimensions; Disease; Emigrations; Excision; Foundations; Functional disorder; Future; Human; ITGAM gene; Immune; Immune response; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Injury; Ischemia; Kinetics; Kupffer Cells; Liver; Mediating; Modeling; Molecular; Mus; Necrosis; Operative Surgical Procedures; Outcome; Pathogenesis; Pattern; Pattern recognition receptor; Phagocytosis; Play; Process; Public Health; Recovery; Reperfusion Injury; Research; Resolution; Role; Seminal; Staging; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transplantation; Trauma; Warm Ischemia; base; cell injury; design; driving force; immune activation; immune function; in vivo; liver function; liver inflammation; liver ischemia; macrophage; monocyte; novel; receptor; reconstitution; research study; response; targeted treatment; tumor

PROJECT SUMMARY The overall object of our research in liver ischemia reperfusion injury (IRI) is to comprehend mechanisms of inflammatory immune activation and resolution. In the last ten years, we have made significant progresses in dissecting molecular mechanisms of liver innate immune response against IR. However, its cellular basis is relatively less-well defined. Kupffer cells (KCs) are liver resident macrophages, which are highly heterogeneous and evolving kinetically in disease processes. Their response against IR has not been fully delineated, particularly in the context of recent finding that tissue resident and monocyte-derived infiltrating macrophages are distinctive in their lineages and functions. Our recent analysis of KC/macrophage subsets in IR livers reveals that liver inflammatory immune activation is associated with not only increases/activations of infiltrating macrophages (iMØs), but also a drastic depletion of resident KCs (KCs). The opposite, i.e., contraction of iMØs and recovery of KCs, is associated with the resolution of liver inflammation. Additionally, M1 polarization is evident in the activation stage, and M2 polarization in the resolution stage of liver immune response in both liver macrophage subsets. The purpose of this exploratory project is to perform proof of principle experiments to establish functional significance of KC depletion in liver IRI, and determine potential mechanisms of KC homeostatic functions in livers against IR. We hypothesize that IR triggers KC necroptosis which constitutes a key mechanism of liver inflammatory immune activation and functions in synergy with the infiltration and activation of iMØs. Additionally, KCs execute the homeostatic function in liver IRI by phagocytosis of apoptotic/necrotic cells, which regulates KC innate immune activation and promotes their polarization towards immune regulatory/reparative type. We will test these two hypothesis in two specific aims. Our study will be the first to analyze specifically responses and functions of liver resident macrophages in IRI. Results will further our understanding of the disease pathogenesis, and potentially provide novel rationale to design appropriate cell-targeted therapies to ameliorate liver IRI.

项目摘要 我们在肝缺血再灌注损伤（IRI）研究的总体对象是理解机制 炎症免疫激活和分辨率。在过去的十年中，我们在 剖析肝脏先天免疫反应对IR的分子机制。但是，其细胞基础是 相对较小的定义。 kupffer细胞（KC）是肝居民巨噬细胞，这是高度的 在疾病过程中非均质和动力学发展。他们对IR的反应尚未完全 划定的，特别是在最近发现组织居民和单核细胞介绍的情况下 巨噬细胞在其谱系和功能中是独特的。我们最近对KC/巨噬细胞子集的分析 红外肝脏表明肝脏炎性免疫激活不仅与增加/激活有关 渗透巨噬细胞（IMøs），但也急剧耗尽了居民KCS（KCS）。相反，即 IMøs的收缩和KC的恢复与肝脏注射的分辨率有关。此外， M1极化是激活阶段的证据，而M2极化在肝脏免疫的分辨率阶段 两种肝巨噬细胞子集的反应。这个探索项目的目的是执行 主要实验在肝脏IRI中建立KC耗竭的功能意义，并确定潜力 肝脏对IR的KC稳态功能的机制。我们假设IR触发KC 坏死性构成肝脏炎性免疫激活和功能的关键机制 与IMøs的渗透和激活协同作用。此外，KCS执行体内平衡 通过凋亡/坏死细胞的吞噬作用在肝脏IRI中的功能，该细胞调节KC先天免疫 激活并促进其对免疫调节/修复类型的极化。我们将测试 这两个假设在两个具体目标中。我们的研究将是第一个分析特别响应的研究 IRI中肝居民巨噬细胞的功能。结果将进一步我们对疾病的理解 发病机理，并有可能为设计适当的细胞靶向疗法设计为新颖的理由 改善肝脏IRI。