Defining The Macrophage-Regulatory T Cell Axis That Promotes Fibrosis Resolution in the Liver

定义促进肝脏纤维化消退的巨噬细胞调节 T 细胞轴

• 批准号: MR/J010766/1
• 负责人: Stuart Forbes
• 金额: $ 199.51万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ010766%2F1
• 关键词: Defining; Macrophage; Regulatory; Cell; Axis

Virtually all long term liver disease, including inborn errors of metabolism and diseases where the immune system attacks the liver through metabolic diseases associated with diabetes, result in scarring of the liver (termed fibrosis) and ultimately advanced scarring (termed cirrhosis). As a result liver scarring is now a common cause of death in the UK and the western world. Indeed, it has been estimated that up to 45% of deaths in the west are the result either directly or indirectly of tissue scarring, including that which occurs in the liver. Previously believed to be irreversible, our laboratory has demonstrated that the scar within the liver is dynamic and, in certain circumstances, is susceptible to break down with a return of a more normal liver architecture and more normal liver function. Critical to this change is a cell called the macrophage. Although the macrophage has been known to promote inflammation and to drive the development of scarring for many years, recently we and others have demonstrated that it is also critical to the breakdown of scar tissue by producing the chemicals which degrade the scar. If we could harness this macrophage function, we would have identified a novel therapeutic approach to the treatment of liver and potentially tissue scarring generically. This application describes a programme of work to further understand what drives the macrophage to become scar degrading and therefore valuable as a therapy. We will study the interaction of the macrophage with another key immune cell type -the regulatory T-cells, which are likely to be important in terminating inflammation and creating the conditions in which resolution of scarring can occur. This work is particularly exciting as, for the first time we will be looking at the cell and molecular "switch" which changes an inflammatory damaging process to one in which remodelling and a return of normal function can take place. We know remarkably little about this switch and yet by piecing together the molecular mechanisms we may open the door to new therapies applicable not just to scarring, but to other disease processes in which inflammation is prominent and damaging. Finally, we will look at a signalling axis within the macrophage for which there are already licensed drugs and which may be amenable to manipulation to achieve our desired tool, the scar degrading macrophage. If we are able to show that existing drugs (currently used for an alternative indication) can drive the macrophages to degrade scars, then these drugs could rapidly come to clinical trials as the important asessments of their effects and side effects are already known, defined as safe and in consequence the drugs are fully licensed.

事实上，所有长期肝病，包括先天性代谢缺陷和免疫系统通过与糖尿病相关的代谢性疾病攻击肝脏的疾病，都会导致肝脏疤痕（称为纤维化）并最终导致晚期疤痕形成（称为肝硬化）。因此，肝脏疤痕现已成为英国和西方世界的常见死亡原因。事实上，据估计，西方高达 45% 的死亡是直接或间接由组织疤痕（包括肝脏中发生的疤痕）造成的。以前被认为是不可逆转的，我们的实验室已经证明，肝脏内的疤痕是动态的，在某些情况下，随着更正常的肝脏结构和更正常的肝功能的恢复，很容易分解。这种变化的关键是一种称为巨噬细胞的细胞。尽管巨噬细胞多年来一直被认为会促进炎症和驱动疤痕形成，但最近我们和其他人已经证明，它通过产生降解疤痕的化学物质，对疤痕组织的分解也至关重要。如果我们能够利用巨噬细胞的这种功能，我们就可以找到一种新的治疗方法来治疗肝脏和潜在的组织疤痕。该申请描述了一个工作计划，以进一步了解是什么驱动巨噬细胞降解疤痕，因此具有作为治疗的价值。我们将研究巨噬细胞与另一种关键免疫细胞类型（调节性 T 细胞）的相互作用，调节性 T 细胞可能对终止炎症和创造消除疤痕的条件很重要。这项工作特别令人兴奋，因为我们将第一次观察细胞和分子“开关”，它将炎症损伤过程改变为可以发生重塑和恢复正常功能的过程。我们对这种转变知之甚少，但通过拼凑分子机制，我们可能会打开新疗法的大门，新疗法不仅适用于疤痕形成，还适用于炎症突出且具有破坏性的其他疾病过程。最后，我们将研究巨噬细胞内的信号轴，该信号轴已经获得许可的药物，并且可以通过操纵来实现我们所需的工具，即疤痕降解巨噬细胞。如果我们能够证明现有药物（目前用于替代适应症）可以驱动巨噬细胞降解疤痕，那么这些药物可以迅速进入临床试验，因为其作用和副作用的重要评估已经已知，被定义为安全的，因此这些药物获得了充分许可。

项目成果

Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.

• DOI: 10.1038/nm.2667
• 发表时间: 2012-03-04
• 期刊: Nature medicine
• 影响因子: 82.9

ECAT-V: where clinical and research training meet.

ECAT-V：临床和研究培训的结合点。

• DOI: 10.1136/vr.f6185
• 发表时间: 2013
• 期刊: The Veterinary record
• 作者: Argyle DJ

The STAT3-IL-10-IL-6 Pathway Is a Novel Regulator of Macrophage Efferocytosis and Phenotypic Conversion in Sterile Liver Injury.

STAT3-IL-10-IL-6途径是无菌肝损伤中巨噬细胞吞噬作用和表型转化的新型调节剂。

• DOI: 10.4049/jimmunol.1701247
• 发表时间: 2018-02-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Campana L;Starkey Lewis PJ;Pellicoro A;Aucott RL;Man J;O'Duibhir E;Mok SE;Ferreira-Gonzalez S;Livingstone E;Greenhalgh SN;Hull KL;Kendall TJ;Vernimmen D;Henderson NC;Boulter L;Gregory CD;Feng Y;Anderton SM;Forbes SJ;Iredale JP
• 通讯作者: Iredale JP

A "good death" with irreversible liver disease: Talking with patients and families about deteriorating health and dying.

不可逆肝病的“美好死亡”：与患者和家属谈论健康状况恶化和死亡。

• DOI: 10.1002/cld.479
• 发表时间: 2015
• 期刊: Clinical liver disease
• 作者: Boyd K

Standing down the guard: stellate cells leave quietly.

• DOI: 10.1053/j.gastro.2012.08.014
• 发表时间: 2012-10
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: N. Henderson;J. Iredale