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Targeting E-prostanoid 3 receptor ameliorates liver fibrosis through enhancing adhesion and cytotoxicity of NK cells toward HSCs

ABSTRACT: Natural killer (NK) cells exhibit anti-fibrotic properties in liver fibrosis (LF) by suppressing activated hepatic stellate cell (HSC) populations. Prostaglandin (PG) E2 plays a dual role in innate and adaptive immunity. E-prostanoid 3 receptor (EP3) was markedly downregulated in NK cells from liver fibrosis mice and patients with liver cirrhosis. NK cell-specific deletion of EP3 aggravated hepatic fibrogenesis in mouse models of LF. For an in-depth analysis of the molecular alterations mediated by EP3 in NK cells, single-cell RNA sequencing (scRNA-seq) was performed using CD27+CD11b+ NK cells. GO, KEGG, GSEA revealed that the adhesion signaling pathway was downregulated in EP3-deficient NK cells. This phenotype was confirmed by qRT-PCR and function experiments. Thus, EP3 is required for adhesion and cytotoxicity of NK cells toward HSCs and may serve as a therapeutic target for the management of LF.

ORGANISM(S): Mus musculus

PROVIDER: GSE196864 | GEO | 2022/02/19

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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Targeting E-prostanoid 3 receptor ameliorates liver fibrosis through enhancing adhesion and cytotoxicity of NK cells toward HSCs

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