Evaluation of Innate Lymphoid Cell subsets and Aryl hydrocarbon Receptor-signaling in mouse models of liver damage and regeneration

小鼠肝损伤和再生模型中先天淋巴细胞亚群和芳烃受体信号传导的评估

• 批准号: 320379802
• 负责人: Professorin Dr. Adelheid Cerwenka
• 金额: --
• 依托单位: Lehrstuhl für Immunbiochemie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/320379802?language=en
• 关键词: Evaluation; Innate; Lymphoid; Cell; subsets

The liver is a unique organ with important metabolic and immune functions that due to its distinctive anatomic position is constantly exposed to damaging biological and chemical agents. In both liver damage and regeneration, the immune system plays a significant part. Innate lymphoid cells (ILCs) are considered to be early responders to tissue damage. Besides their tissue protective role, their responses could also be detrimental, contributing to the development of various pathologies, including cancer. The sensors expressed by ILCs and modules of ILC activation in the liver tissue are still incompletely defined. Moreover, the control mechanism(s) poising ILC responses towards tissue protection or destruction remain rather elusive. During the first two years of funding period 1, we investigated the Aryl-hydrocarbon Receptor (AhR)-driven responses of the dominant ILC subsets in liver, Natural Killer (NK) cells and liver-resident ILC1s, in the context of diet-induced chronic liver damage. Our results reveal that conditional deletion of AhR in NKp46-expressing cells, comprising both NK cells and ILC1s in liver, significantly reduced liver damage. This phenotype was associated with decreased accumulation of NK/ILC1s in the liver tissue. AhR activation in NK/ILC1 resulted in enhanced levels of the cytokine IL-10, of the chemokine CCL2 and in increased numbers of Ly6C-expressing CCR2+ inflammatory monocytes. Neutralization of IL-10 significantly reduced CCL2 production, inflammatory monocyte numbers and liver damage. Thus, our data imply that, in contrast to its well-established suppressing role, IL-10 functions as a central effector regulator downstream of the AhR-mediated NK/ILC1 activation. In the next step, we will address the nature of damage-associated AhR-ligands, and the sources and mechanisms of IL-10 (Work Package A) to complete our understanding of the role of the AhR and NK/ILC1s in chronic liver damage.Extending our results obtained so far, during the second funding period, we will address the role of AhR-driven NK/ILC1 responses in liver regeneration. We will apply the well-established model of partial hepatectomy, in which hepatocyte-mediated regeneration restores liver mass and function within two weeks after surgery. We will address whether AhR-mediated regulation of NK/ILC1 function affects regeneration and immune cell repopulation of the healthy liver tissue (Work Package B), and of diseased liver tissue (Work Package C), mimicking resection performed in patients with liver disease. The data obtained during the whole project (funding period 1 and 2) will help understanding NK/ILC1 function in tissue damage vs regeneration and the role of AhR as a microenvironmental sensor in NK/ILC1s. This knowledge could be of high relevance for designing innovative treatments for patients with liver disease.

肝脏是一个独特的器官，具有重要的代谢和免疫功能，由于其独特的解剖位置，经常暴露在破坏性的生物和化学物质中。在肝脏损伤和再生方面，免疫系统都起着重要作用。先天淋巴样细胞(ILCs)被认为是对组织损伤的早期反应。除了它们的组织保护作用外，它们的反应也可能是有害的，有助于包括癌症在内的各种病理的发展。肝组织中ILC表达的感受器和ILC激活模块仍未完全确定。此外，控制机制(S)平衡ILC对组织保护或破坏的反应仍然相当难以捉摸。在资助期1的头两年，我们在饮食诱导的慢性肝损伤的背景下，研究了肝脏中主要的ILC亚群、自然杀伤(NK)细胞和驻留在肝脏的ILC1的芳香烃受体(AhR)驱动的反应。我们的结果显示，在表达NKp46的细胞中有条件地删除AhR，包括肝脏中的NK细胞和ILC1s，显著减少了肝脏损伤。这种表型与NK/ILC1s在肝组织中的积聚减少有关。NK/ILC1中AHR的激活导致细胞因子IL-10和趋化因子CCL2水平升高，并导致表达Ly6C的CCR2+炎性单核细胞数量增加。中和IL-10可显著减少CCL2的产生、炎性单核细胞数和肝损伤。因此，我们的数据暗示，与其公认的抑制作用相反，IL-10作为AhR介导的NK/ILC1激活下游的中心效应调节因子发挥作用。下一步，我们将讨论损伤相关的AhR配体的性质，以及IL-10的来源和机制(工作包A)，以完成我们对AhR和NK/ILC1在慢性肝损伤中作用的理解。在第二个资助期，我们将扩展我们已有的结果，讨论AhR驱动的NK/ILC1反应在肝脏再生中的作用。我们将应用公认的肝部分切除模型，在该模型中，肝细胞介导的再生在术后两周内恢复肝脏质量和功能。我们将讨论AhR介导的NK/ILC1功能调节是否会影响健康肝组织(工作包B)和患病肝组织(工作包C)的再生和免疫细胞再繁殖，类似于肝病患者的切除。在整个项目(资助期1和2)期间获得的数据将有助于了解NK/ILC1在组织损伤和再生中的功能，以及AhR作为微环境传感器在NK/ILC1s中的作用。这些知识可能对设计肝病患者的创新治疗具有很高的相关性。