Trafficking of monocytes and their differentiation to dendritic cells and macrophages in the human liver

大多数肝脏疾病的发生是由从血液中募集到肝脏中的白色血细胞介导的不受控制的炎症的结果。白色血细胞通过通道或窦状隙进入肝脏，通道或窦状隙由称为内皮细胞的特化细胞排列，白色细胞必须结合内皮细胞并在内皮细胞之间迁移，然后才能进入肝脏组织。我们认为，这一过程将a）决定招募的细胞的性质，B）决定这些细胞如何被激活，从而决定肝损伤的结果。我们已经开发了复杂的试管模型，其中人类肝细胞的组合在模拟患病肝窦内环境的特定条件下生长。我们将使用这些模型来研究白色细胞是如何募集的，以及在募集过程中与窦状隙细胞的相互作用如何定义细胞的激活状态。了解这个过程将阐明为什么在某些情况下，白色血细胞可以促进受损肝脏的修复，而在其他情况下，它们会放大肝损伤。我们希望利用这些信息来开发新的治疗方法，以操纵肝脏中的白色血细胞，有利于修复而不是继续肝损伤，从而逆转炎症性肝病并预防肝硬化。

Most liver diseases occur as a consequence of uncontrolled inflammation mediated by white blood cells recruited into the liver from the blood. White blood cells enter the liver via channels or sinusoids that are lined by specialised cells called endothelial cells which the white cells must bind to and migrate between before they can enter liver tissue. We propose that this process will a) determine the nature of the cells recruited and b) determine how those cells become activated and thereby the outcome of liver injury. We have developed complex test tube models in which combinations of human liver cells are grown under particular conditions that mimic the environment within the diseased liver sinusoids. We will use these models to investigate how white cells are recruited and how interactions with sinusoidal cells can define the activation status of the cells during their recruitment. Understanding this process will elucidate why in some circumstances white blood cells can promote the repair of the damaged liver whereas in other circumstances they amplify liver injury. We hope to use this information to develop new therapies to manipulate white blood cells in the liver in favour of repair rather than continuing liver damage and thereby to reverse inflammatory liver disease and prevent liver cirrhosis.