The Role of Tissue-resident Hepatic Macrophages in the Resolution of Chronic Liver Injury

肝硬化是由各种原因引起的慢性肝损伤的结果，其特征是进行性瘢痕形成，最终导致肝功能衰竭。肝硬化已经被英国政府强调为过早死亡的“五大”原因之一，并且令人担忧的是，死亡率继续增加（自1970年以来超过400%），尽管由于其他常见原因（如心脏病或癌症）导致的死亡同时减少。目前的治疗方法并不令人满意，选择仅限于清除潜在病因和少数肝移植。然而，现在有证据表明，几乎所有的肝脏疾病，即使是先进的疤痕至少可以部分解决。因此，通过研究控制这种疤痕消退的机制，我们可能会开发出急需的新疗法，以改善肝硬化，预防肝衰竭和过早死亡。巨噬细胞是免疫系统的细胞，具有许多亚型和广泛的生物学功能。它们存在于身体的所有器官中，也可以来自血液。巨噬细胞对于去除肝脏和其他器官中的瘢痕组织至关重要。因此，通过了解这些疤痕解决巨噬细胞的生物学，我们可以潜在地增加它们的数量和/或活性，对器官功能产生有益的影响。然而，为了针对适当的群体并限制潜在治疗的副作用，我们必须充分了解不同巨噬细胞群体的功能。肝脏中巨噬细胞亚群的主要区别特征之一是它们的起源。常驻肝巨噬细胞在出生前形成，在胚胎发育期间，并维持自己到成年。或者，响应于肝损伤，细胞（称为单核细胞）从血液中募集到受损的肝脏中，并成为巨噬细胞的单独群体。我以前的研究发现，血液来源的肝脏巨噬细胞群体负责慢性肝损伤后疤痕消退的早期阶段。肝损伤也会引起肝巨噬细胞的变化，但这一群体在瘢痕消退中的作用尚未研究。因此，本研究的目的是研究慢性肝损伤后驻留肝巨噬细胞在瘢痕消退中的作用，我将开发小鼠模型，在那里我可以识别驻留肝巨噬细胞，并将其与血液来源的肝巨噬细胞区分开来。能够区分这些细胞类型对于能够将功能归因于任一群体至关重要。为了确定每个巨噬细胞群体的功能，我将使用这些小鼠模型选择性地去除驻留的或血液来源的肝脏巨噬细胞，并评估这对肝脏损伤恢复的影响。为了阐明肝脏巨噬细胞群体如何介导它们的作用，我将分离巨噬细胞群体并分析它们表达的基因。同样地，我将从接受肝移植的患者的人肝硬化肝脏中分离和分析巨噬细胞，并将其与小鼠巨噬细胞结果进行比较。这将使我能够确定小鼠和人类肝脏疾病之间保守的途径，这对于开发潜在的治疗方法至关重要。最后，我将使用新的显微镜技术来检查巨噬细胞在真实的时间内的活小鼠肝脏慢性损伤后。这将产生对巨噬细胞定位对功能的影响的见解。通过完成这项研究，我将描述常驻肝脏巨噬细胞在慢性损伤后肝脏瘢痕消退中的作用。这将是我们对控制慢性肝损伤解决机制的理解的一个重大进展，并有望在开发有针对性的治疗策略以改善肝功能和降低死亡率之前。

Liver cirrhosis is the result of chronic liver damage from a variety of causes and is characterised by progressive scarring which eventually causes liver failure. Cirrhosis has been highlighted by the UK government as one of the "Big Five" causes of premature death and, worryingly, the rates of death continue to increase (over 400% since 1970) despite simultaneous reductions in death due to other common causes such as heart disease or cancer. Current treatments are unsatisfactory with options limited to removal of the underlying cause and liver transplantation for a select few. However, there is now evidence in virtually all liver diseases that even advanced scarring can at least partially resolve. Hence, by studying the mechanisms controlling this scar resolution, we could potentially develop badly-needed new treatments to improve cirrhosis and prevent liver failure and premature death.Macrophages are cells of the immune system with numerous subtypes and a wide range of biological functions. They reside in all organs of the body and can also be derived from blood. Macrophages are essential for the removal of scar tissue in the liver and other organs. Thus, by understanding the biology of these scar resolving macrophages, we could potentially enhance their number and/or activity, with a beneficial effect on organ function. However, in order to target the appropriate population and limit side effects from potential treatments, it is imperative that we have a full understanding of the function of differing macrophage populations. One of the main distinguishing features of macrophage subpopulations in the liver is their origin. Resident liver macrophages are formed prior to birth, during embryological development, and maintain themselves into adulthood. Alternatively, in response to liver injury, cells (called monocytes) are recruited from the blood into the damaged liver and become a separate population of macrophages. My previous research identified that a population of blood-derived liver macrophages was responsible for the early phase of scar resolution following chronic liver damage. Liver injury also induces changes in resident liver macrophages, but the role of this population in scar resolution has not been studied. Thus, the objective of this proposed research will be to study the role of resident liver macrophages in scar resolution after chronic liver injury.I will develop mouse models where I can identify resident liver macrophages and differentiate them from liver macrophages derived from blood. Being able to distinguish these cell types is essential to be able to attribute functions to either population. To determine the function of each macrophage population, I will use these mouse models to selectively remove either resident or blood-derived liver macrophages and assess the effect this has on the recovery from liver damage. To clarify how liver macrophage populations mediate their effects, I will isolate macrophage populations and analyse which genes they express. Similarly, I will isolate and analyse macrophages from human cirrhotic livers in patients undergoing liver transplantation, and compare them to the mouse macrophage results. This will enable me to identify pathways conserved between mouse and human liver disease, which is critical for development of potential treatments. Finally, I will use novel microscope technology to examine macrophages in real time within the livers of live mice following chronic injury. This will yield insights into the effects of macrophage localisation on function.By completing this research, I will have characterised the role of resident liver macrophages in the regression of liver scarring after chronic injury. This will be a major advance in our understanding of mechanisms controlling the resolution of chronic liver damage, and will hopefully precede the development of targeted treatment strategies to improve liver function and reduce mortality.