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

点击翻译按钮获取中文摘要

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.