title: Immune-endothelial axis in liver homeostasis and inflammation
creator: See, Jia-Xiang
subject: ddc-570
subject: 570 Life sciences
description: Liver is a zonated and highly vascularized organ, enriched with immune cells. Liver sinusoidal endothelial cells (LSECs) form the microvasculature in the liver, comprising the major non-parenchymal liver cells. They constitute the sinusoids where immune cells reside in. In the liver, there are two major subsets of innate lymphocytes, which are circulating natural killer (NK) cells and tissue-resident innate lymphoid cell 1 (ILC1s). As LSECs and innate lymphocytes are in close proximity, LSECs and NK cells, and ILC1s, might regulate each other functions in liver homeostasis and disease.      Here, I investigated LSEC-immune cell crosstalk in steady-state and liver disease. I illustrated a novel mechanism of LSECs to act as a non-immune cell bridging innate and adaptive immunity in liver homeostasis. LSECs expressed heterogeneous amounts of major histocompatibility II (MHC II) in a zonated manner, mainly in midzonal and pericentral acini. The MHC II expression on LSECs was dependent on interferon gamma (IFN-γ), produced by ILC1s, NK cells, and NKT cells in steady-state. The reduction of MHC II expression on LSECs correlated with an increased naïve CD4+ T cell and a decreased memory CD4+ T cell frequency in the liver. Hence, IFN-γ secreted by innate lymphocytes regulates naive to memory T cell differentiation, by maintaining MHC II expression on LSECs in the liver in steady-state.    In addition, LSECs induced transcriptomic and phenotypic changes of NK cells after co-culture. They also primed NK cells to produce a higher amount of IFN-γ upon stimulation. In a lipopolysaccharide (LPS)-induced acute liver injury model, LSECs displayed ‘activated’ phenotypes by upregulation of surface proteins involved in regulating immune functions, mimicking phenotypes of LSECs stimulated by IFN-γ. In addition, LSECs also upregulated adhesion molecules in the LPS liver injury model, important for NK cell and monocyte recruitment into the liver during the disease. Furthermore, in aged mice, conditional deletion of Herpesvirus Entry Mediator (HVEM) in LSECs led to splenomegaly.    In summary, my study highlights LSECs as the center mediating innate and adaptive immune responses in homeostasis, inflammation, and disease. I describe LSECs as an unorthodox non-immune player to regulate liver immunology, which provides a singular insight of how the stromal microenvironment shapes immune cell functions.
date: 2023
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/32073/1/JXS_Full_Thesis_Final%20Version.pdf
identifier: DOI:10.11588/heidok.00032073
identifier: urn:nbn:de:bsz:16-heidok-320730
identifier:   See, Jia-Xiang  (2023) Immune-endothelial axis in liver homeostasis and inflammation.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/32073/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng