Authors:	Hessel, Christian
Title:	Role of the Interleukin-2 pathways in hepatic innate lymphoid cells during steady state, fibrosis and hepatocellular carcinoma
Online publication date:	17-Nov-2021
Year of first publication:	2021
Language:	english
Abstract:	The immune system is an essential part of our body that is able to combat diverse attacks like viruses, bacteria and tumor cells. At the same time it needs a tight regulation as an overwhelming immune response can harm healthy cells and organs whereas an improper immune response can lead to the spread of invading pathogens within the body. Cytokines are able to regulate immune responses. One of them, namely interleukin- (IL)2, is mainly secreted by cluster of differentiation (CD)4 T cells and consumed by regulatory T cells (Tregs), both cell compartments of the adaptive immune system (Gordon et al., 1965). It was just recently described that IL2 can also act on cells of the innate immune system, mainly group 1 innate lymphoid cells (ILCs) (Gasteiger, Hemmers, Bos, et al., 2013; Gasteiger, Hemmers, Firth, et al., 2013). The exact role of IL2 on group 1 ILCs still remains largely unknown. The aim of this thesis was to establish mainly flow cytometric methods to study hepatic immune cells, herewith especially group 1 ILCs, in the course of diet- and toxin-driven liver disease models. Additionally, the role of group 1 ILCs within these models should be characterized with the help of genetic mouse models. IL2 and its receptor subunit CD25 were studied in regard of their potential to regulate the group 1 ILC-mediated immune response in conditional knockout mice. It can be shown that in different longterm models of liver fibrosis ILC1s upregulated CD25. Models investigated are cholinedeficient high-fat diet (CD-HFD), high-fat high-carb (HFHC) diet and carbon tetrachloride (CCl4)- and thioacetamide (TAA)-induced liver fibrosis. We performed these experiments with wildtype (WT) mice and genetic knockouts (KOs) specifically depleting either IL2 or CD25 in natural killer (NK)p46+ group 1 ILCs. Group 1 ILCs showed a higher proliferation after long-term CD-HFD and at the same time produced less cytokines like interferon gamma (IFNg), IL2 and tumor necrosis factor alpha (TNFa). Unexpectedly, depletion of group 1 ILCs led to reduced inflammation and increased anti-inflammatory M2-like macrophages (MPs) during CD-HFD and an increase in M2-like MPs, granulocyte (Gr)1+ cells and DCs in the reversal phase of CCl4-induced liver fibrosis. Depletion of CD25 in group 1 ILCs led to a slight increase in IL2 production from ILC1s whereas the overall production of IL2 by ILC1s tremendously decreased after CCl4-induced liver fibrosis. Therefore, IL2-depletion on group 1 ILCs seems to affect mainly the innate immune cell compartment. M2-like MPs increase during the acute phase of CCl4-induced liver fibrosis whereas M1-like MPs increase during the reversal phase. Further experiments focused on the role of matrix 14 metalloproteases (MMPs) for ILC1 function. MMP3 KO mice showed altered proliferation and CD25 expression of ILC1s during the acute and reversal phase of CCl4-induced liver fibrosis. In summary, the presented work highlights diverse roles of ILC1s and ILC-derived IL2 during the acute phase of liver fibrosis and in the tissue healing phase.
DDC:	570 Biowissenschaften 570 Life sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 10 Biologie
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-6452
URN:	urn:nbn:de:hebis:77-openscience-74bc84bc-6336-4e1f-b484-8fadcb7f38a31
Version:	Original work
Publication type:	Dissertation
License:	CC BY-ND
Information on rights of use:	https://creativecommons.org/licenses/by-nd/4.0/
Extent:	X, 72, v Blätter
Appears in collections:	JGU-Publikationen