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

肝硬化是由多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，最终导致肝衰竭。肝硬化已被英国政府列为过早死亡的“五大”原因之一，令人担忧的是，尽管心脏病或癌症等其他常见原因导致的死亡率同时减少，但死亡率仍在继续增加（自1970年以来超过400%）。目前的治疗方法并不令人满意，选择仅限于去除根本原因和肝移植。然而，现在有证据表明，在几乎所有的肝脏疾病中，即使是晚期的疤痕也至少可以部分解决。因此，通过研究控制这种疤痕消退的机制，我们有可能开发出急需的新疗法来改善肝硬化，预防肝功能衰竭和过早死亡。巨噬细胞是免疫系统的细胞，具有多种亚型和广泛的生物学功能。它们存在于身体的所有器官中，也可以从血液中提取。巨噬细胞对于清除肝脏和其他器官的疤痕组织至关重要。因此，通过了解这些疤痕溶解巨噬细胞的生物学，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，为了针对适当的人群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特征之一是它们的起源。常驻肝巨噬细胞在出生前，胚胎发育期间形成，并维持到成年。或者，作为对肝损伤的反应，细胞（称为单核细胞）从血液中被招募到受损的肝脏中，成为一个单独的巨噬细胞群。我之前的研究发现，血液来源的肝巨噬细胞群与慢性肝损伤后瘢痕消退的早期阶段有关。肝损伤也会引起常驻肝巨噬细胞的变化，但这一群体在疤痕消退中的作用尚未得到研究。因此，本研究的目的是研究常驻肝巨噬细胞在慢性肝损伤后疤痕消退中的作用。我将开发小鼠模型，在那里我可以识别常驻肝巨噬细胞，并将它们与来自血液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种群至关重要。为了确定每个巨噬细胞群的功能，我将使用这些小鼠模型选择性地去除常驻或血源性肝巨噬细胞，并评估这对肝损伤恢复的影响。为了阐明肝巨噬细胞群体如何介导其作用，我将分离巨噬细胞群体并分析它们表达的基因。同样，我将从肝移植患者的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的保守途径，这对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实时检测慢性损伤后活小鼠肝脏内的巨噬细胞。这将深入了解巨噬细胞定位对功能的影响。通过完成这项研究，我将描述常驻肝巨噬细胞在慢性损伤后肝瘢痕消退中的作用。这将是我们对控制慢性肝损伤解决机制的理解的重大进展，并有望先于有针对性的治疗策略的发展，以改善肝功能和降低死亡率。

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.