The role of P2RY8 in B cell-endothelial crosstalk in primary biliary cholangitis

About This Grant

SUMMARY Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease in which the body’s immune system attacks the small bile ducts, leading to cholestasis (toxic bile accumulation), fibrosis, and ultimately liver failure. A hallmark of PBC is the activation of autoreactive B cells that produce anti-mitochondrial antibodies (AMAs), but the mechanisms that regulate B-cell activation within the liver microenvironment remain poorly defined. Recent work from our group and others indicates that liver lymphatic endothelial cells (LyECs), which line the lymphatic vessels running alongside bile ducts, play an active role in regulating immune cell trafficking and tolerance. In our preliminary analysis of single-cell RNA-seq data from human PBC livers, we identified striking upregulation of P2RY8, a G-protein–coupled receptor (GPCR), in both LyECs and B cells. P2RY8, an understudied gene listed in this RFA, couples to the Gα13–RhoA pathway to control immune cell positioning and is activated by S-geranylgeranyl-L-glutathione (GGG), a naturally occurring lipid metabolite in the mevalonate pathway. Although P2RY8 regulates B-cell migration in lymphoid tissues, its role in the liver or vascular endothelium has never been explored. This high-risk, high-reward R03 project will define how P2RY8 signaling reprograms LyEC phenotype (Aim 1) and how LyEC P2RY8 activity influences B-cell activation and AMA production (Aim 2). By uncovering a novel LyEC–B-cell communication axis, this work will establish a new conceptual framework for autoimmune cholangiopathies and lay the foundation for future studies exploring P2RY8 as a therapeutic target in PBC.