The role of conventional and liver resident NK cells in drug-induced liver injury and in the regulation of ILC2 cells

常规NK细胞和肝脏常驻NK细胞在药物性肝损伤和ILC2细胞调节中的作用

• 批准号: 397052788
• 负责人: Professor Dr. Jan G. Hengstler
• 金额: --
• 依托单位: Forschungsbereich Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/397052788?language=en
• 关键词: role; conventional; liver; resident; NK

The immune system can significantly contribute to liver damage, not only in the context of chronic viral infections, but also during drug induced liver injury (DILI). Here we focus on the role of liver resident (lrNK) and conventional NK cells (cNK) in the context of DILI and on the role of group 2 innate lymphoid cells (ILC2) during liver fibrosis. Our application is based on the hypothesis that NK cells play a dual role in liver injury. Based on our preliminary data we hypothesize that NK cells can contribute to drug-induced liver injury via the killing of hepatocytes after drug-induced up-regulation of ligands for activating NK cell receptors. Additionally, liver injury is associated with an expansion of ILC2 cells, which can contribute to liver fibrosis. Previous publications have shown that the expansion of ILC2 cells can be inhibited by Interferons. Together with our preliminary data we propose that liver NK cells can control and regulate ILC2 cells and thereby reduce liver fibrosis. To test these two hypotheses we have set up several in vivo and in vitro experimental systems using mouse and human liver NK cells in order to comprehensively characterize the interactions between NK cells, hepatocytes and ILC2. The experimental design allows us to directly compare the phenotype and function of conventional circulating cells (cNK) with tissue resident innate lymphocytes (lrNK) and to investigate the function and the dynamics of these cells during liver injury. Our results will be essential to understand how the opposing activities of liver NK cells with their protective effect during fibrosis and their potential pathological impact during drug induced liver injury are balanced.

免疫系统不仅在慢性病毒感染的情况下，而且在药物诱导的肝损伤（DILI）期间，都可以显著地促进肝损伤。在这里，我们集中在肝居民（lrNK）和传统的NK细胞（cNK）的DILI的背景下的作用和第2组先天淋巴细胞（ILC2）在肝纤维化过程中的作用。我们的应用是基于NK细胞在肝损伤中发挥双重作用的假设。基于我们的初步数据，我们假设NK细胞可以通过药物诱导的激活NK细胞受体的配体上调后杀死肝细胞而导致药物诱导的肝损伤。此外，肝损伤与ILC2细胞的扩增有关，这可能导致肝纤维化。先前的出版物已经表明，ILC2细胞的扩增可以被干扰素抑制。结合我们的初步数据，我们提出肝脏NK细胞可以控制和调节ILC2细胞，从而减少肝纤维化。为了验证这两个假设，我们已经建立了几个体内和体外实验系统，使用小鼠和人的肝脏NK细胞，以全面表征NK细胞，肝细胞和ILC2之间的相互作用。实验设计使我们能够直接比较常规循环细胞（cNK）与组织固有淋巴细胞（lrNK）的表型和功能，并研究这些细胞在肝损伤过程中的功能和动力学。我们的研究结果对于了解肝脏NK细胞的相反活性及其在纤维化过程中的保护作用和药物诱导的肝损伤过程中的潜在病理影响是如何平衡的至关重要。