Liver Dendritic Cells in Tolerance and Immunity

描述（由申请人提供）：肝缺血再灌注（I/R）在部分肝切除术、肝移植和低血容量性休克后引起不良的高炎症反应。目前还没有有效的治疗方法。虽然树突状细胞（dc）现在被认为是全身免疫和炎症的主要介质，但我们对肝脏dc的了解还很初级。在我们最初的5年资助中，我们主要建立了新分离的小鼠和人类肝脏dc的T细胞刺激能力。在这个额外5年资金的竞争性更新申请中，我们将研究肝dc在肝脏炎症中的先天作用。toll样受体（TLRs）是一种存在于免疫细胞上的进化保守蛋白，可识别病原体、免疫危险信号和内源性核酸，并随后激活先天免疫。我们已经发现TLR9，一种检测低甲基化细菌CpG基序和内源性DNA的细胞内受体，调节肝脏I/R中常规dc的抗炎反应。此外，我们发现浆细胞样dc在I/R中具有保护作用。因此，我们假设内源性配体在肝I/R损伤的免疫发病机制中调节dc。在目的1中，我们将确定常规dc对内源性配体的肝脏I/R调节。在Aim 2中，我们将建立浆细胞样dc对肝脏I/R的保护机制。在Aim 3中，我们将建立人肝脏I/R体外模型中TLR对损伤的要求。提出的实验将增加我们对肝脏炎症机制的认识。我们的研究与人类疾病直接相关，并可能导致TLR阻断剂用于治疗涉及肝脏和其他器官（如心脏、肾脏、肺和脑）的人I/R。

DESCRIPTION (provided by applicant): Liver ischemia reperfusion (I/R) induces an untoward hyperinflammatory response following partial hepatectomy, liver transplantation, and hypovolemic shock. Currently, there are no effective therapies. While dendritic cells (DCs) are now recognized as the principal mediators of immunity and inflammation throughout the body, our understanding of liver DCs has been rudimentary. During our first 5 years of funding, we primarily established the T cell stimulating capacity of freshly isolated mouse and human liver DCs. In this competitive renewal application for an additional 5 years of funding, we will investigate the innate role of hepatic DCs in liver inflammation. Toll-like receptors (TLRs) are evolutionarily conserved proteins present on immune cells that recognize pathogens, immunologic danger signals and endogenous nucleic acids and subsequently activate innate immunity. We have discovered that TLR9, the intracellular receptor that detects hypomethylated bacterial CpG motifs and endogenous DNA, modulates anti-inflammatory responses by conventional DCs in liver I/R. Additionally, we have discovered that plasmacytoid DCs exert protective effects in I/R. Thus, we hypothesize that endogenous ligands regulate DCs in the immunopathogenesis of liver I/R injury. In Aim 1, we will determine the regulation of liver I/R by conventional DCs in response to endogenous ligands. In Aim 2, we will establish the mechanism of protection by plasmacytoid DCs in liver I/R. In Aim 3, we will establish the TLR requirements for injury in an in vitro model of human liver I/R. The proposed experiments will increase our knowledge regarding the mechanisms of hepatic inflammation. Our investigation has direct relevance to human disease and may lead to the use of TLR blockade for the treatment of hu- man I/R that involves the liver and other organs, such as the heart, kidney, lung, and brain. PUBLIC HEALTH RELEVANCE: In this proposal, we will investigate the role of liver dendritic cells and danger signals released by the host during liver inflammation in mice and humans. Our investigations will be useful in identifying new therapies to treat ischemia reperfusion injury that occurs in humans.