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

项目总结 我们对肝脏缺血再灌注损伤(IRI)的研究的总体目标是了解其作用机制。 炎性免疫的激活和消解。在过去的十年里，我们在以下方面取得了重大进展 剖析肝脏抵抗IR先天免疫反应的分子机制。然而，它的细胞基础是 相对不那么明确。Kupffer细胞(KCs)是一种驻留在肝脏的巨噬细胞，具有高度的 疾病过程中的异质性和动态演变。他们对IR的反应还不够充分 描述，特别是在最近发现组织驻留和单核细胞来源的渗透的背景下 巨噬细胞具有独特的谱系和功能。我们最近对KC/巨噬细胞亚群的分析 IR肝脏研究表明，肝脏炎症免疫激活不仅与增加/激活 侵袭巨噬细胞(I？S)，但也急剧耗尽常驻的角质细胞(KCs)。相反，也就是， 肌注S收缩，KCs恢复，与肝脏炎症消退有关。另外， 肝脏免疫激活期M1极化明显，肝免疫解决期M2极化明显 两种肝巨噬细胞亚群的反应。这个探索性项目的目的是为了证明 原则性实验确定KC耗竭在肝脏IRI中的功能意义，并确定潜在的 肝脏KC稳态功能抗IR的机制。我们假设IR触发KC 坏死性下垂是肝脏炎性免疫激活和功能的关键机制 与IM？S的渗透和激活协同作用。此外，KCs还执行动态平衡 吞噬凋亡/坏死细胞调节KC天然免疫在肝脏IRI中的作用 激活并促进其两极分化为免疫调节/修复型。我们将测试 这两个假设有两个具体的目的。我们的研究将是第一个具体分析回应和 肝脏滞留巨噬细胞在IRI中的作用。这些结果将加深我们对这种疾病的了解 发病机制，并有可能为设计适当的细胞靶向疗法提供新的理论基础 改善肝脏IRI。

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.