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Hepatic Stellate Cell Activation after 72hr

ABSTRACT: Chronic liver diseases as non-alcoholic steatohepatitis (NASH)-induced cirrhosis are characterized by an increasing accumulation of stressed, damaged, or dying hepatocytes. Hepatocyte damage triggers the activation of resident immune cells, such as Kupffer cells (KC), as well as the recruitment of immune cells from the circulation towards areas of inflammation. After infiltration, monocytes differentiate into monocyte-derived macrophages (MoMF) which are functionally distinct from resident KC. We herein aim to compare in vitro signatures of polarized macrophages and activated hepatic stellate cells (HSC) with ex vivo derived disease signatures from human NASH. Secondly, we investigate the effects of the secretome of primary human monocytes, macrophages and NK cells on HSC activation, as in particular monocytes and macrophages have often been linked to liver fibrosis progression. IL-4 and IL-13 treatment induced TGF-β1 secretion by macrophages. However, the supernatant transfer did not induce HSC activation. Interestingly, PMA-activated macrophages showed a strong induction of the fibrosis response genes COL10A1 and CTGF, while supernatant of IL-4/IL-13 treated monocytes induced the upregulation of COL3A1 in HSC. Supernatant of PMA-activated NK cells had the strongest effect on COL10A1 induction in HSC, while IL-15 stimulated NK cells reduced the expression of COL1A1 and CTGF. These data indicate that other factors, aside the well-known cytokines and chemokines, are potentially stronger contributors to activation of HSCs and induction of a fibrotic response, indicating a more diverse and complex role of monocytes, macrophages and NK cells in liver fibrosis progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228086 | GEO | 2024/03/20

REPOSITORIES: GEO

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Project description:Gene-expression profiles of hepatic stellate cells isolated from IL15R-alpha knockout mouse IL-15 and its high affinity receptor IL-15Rα are widely expressed in immune cells including dendritic cells and macrophages and non-immune cells such as hepatocytes, oval cells and hepatic stellate cells (HSC). IL-15 signaling has important functions in natural killers (NK), natural killers T (NKT) and cytotoxic T (CD8+T) cell homeostasis and also in liver regeneration. We hypothesized that IL-15 may have a protective role during liver fibrosis progression due to its role in NK cell homeostasis. We compared fibrosis progression in IL-15Rα knockout mice (IL-15RαKO) to wild type mice using two mechanistically distinct models, chronic carbon tetrachloride (CCl4) exposure and bile duct ligation (BDL). Enhanced fibrosis progression was observed in IL-15RαKO mice in both models. Furthermore, using congenic bone marrow transplantation (BMT), we demonstrated an unexpected role for IL-15 signaling in hepatic resident cells for the maintenance of liver NK and CD8+T cell populations. Using this approach, transplanting IL-15RKO hematopoietic cells results in NK defect that surprisingly is not reflected in a change of fibrosis progression. However, chimeric mice with defect of IL-15R on liver resident cells have similar NK defects and significant more fibrosis after CCL4 liver injury. This supports a direct protective, anti-fibrogenic role for IL-15R on one of the radioresistant liver cell populations (hepatocytes, HSC and sessile Kupffer cells). Microarray analysis of IL15RKO HSC suggests up-regulation of collagen transcripts and down-regulation of pathways involved in cell proliferation/survival. Finally, activated HSCs isolated from IL-15RKO mice show increased collagen secretion and as predicted, no changes in the growth curves. In summary, IL-15Rα signaling has an anti-fibrotic effect through both BM-derived and hepatic resident cells. These findings establish a rationale to explore IL-15 signaling in HSC as a potential therapeutic target in liver fibrogenesis.

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Hepatic Stellate Cell Activation after 72hr

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