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

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. Flow sorted splenic CD27+CD11b+ NK cells from two mice from each group (EP3F/F and NKp46CreEP3F/F) were pooled for droplet-based single-cell RNA-seq (10x Genomics platform).