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

项目摘要 我们研究肝脏缺血再灌注损伤（IRI）的总体目标是了解肝脏缺血再灌注损伤的机制。 炎症免疫激活和消退。在过去的十年里，我们在以下方面取得了重大进展： 解剖肝脏固有免疫反应的分子机制。然而，其细胞基础是 相对不太明确。枯否细胞（KCs）是肝脏驻留的巨噬细胞，其高度增殖。 在疾病过程中是异质的和动态进化的。他们对IR的反应还没有完全 描述，特别是在最近发现的背景下，组织驻留和单核细胞来源的浸润 巨噬细胞在它们的谱系和功能上是独特的。我们最近对KC/巨噬细胞亚群的分析表明， IR肝脏显示肝脏炎症免疫激活不仅与肝脏炎症因子的增加/激活有关， 浸润性巨噬细胞（iMCs），但也急剧消耗常驻KC（KC）。相反，即， iM的收缩和KC的恢复与肝脏炎症的消退相关。此外，本发明还 肝脏免疫激活期M1极化明显，消退期M2极化明显， 在两个肝巨噬细胞亚群中的反应。这个探索性项目的目的是证明 原则实验，以确定KC耗竭在肝脏IRI中的功能意义，并确定潜在的 KC的稳态功能在肝脏中对抗IR的机制。我们假设IR触发KC 坏死性凋亡构成肝脏炎症免疫激活和功能的关键机制 与iMIPs的渗透和激活协同作用。此外，KC执行稳态 通过吞噬凋亡/坏死细胞在肝脏IRI中发挥作用，调节KC先天免疫 激活并促进其向免疫调节/修复型极化。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反应， IRI中肝驻留巨噬细胞的功能。结果将进一步加深我们对这种疾病的了解 发病机制，并可能提供新的理论基础，设计适当的细胞靶向治疗， 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.