Macrophage Immune Modulation to Improve Outcome in Obstructive Cholestasis

Cholestatic liver injury from biliary obstruction is a sequela of pediatric and adult liver diseases including biliary atresia, primary sclerosing cholangitis, primary biliary cholangitis, and various genetic etiologies such as Alagille Syndrome. These diseases remain a leading indication for liver transplantation as no therapy exists to prevent disease progression. While immune cells, particularly macrophages play an important role in the pathogenesis of cholestatic liver injury, cell-specific immunotherapies have not been developed.Treatment with the bile acid analogue farnesoid X receptor (FXR) agonist has recently demonstrated a biochemical response in primary biliary cholangitis and primary sclerosing cholangitis; however, direct targeting of the FXR-induced immune pathway has not been evaluated. . To accomplish these objectives, we will perform the following Specific Aims: Aim 1. To define the specific pathogenic human hepatic macrophage subsets in cholestatic liver disease. We will perform scRNA-seq on hepatic leukocytes (CD45+) from cholestatic and non-cholestatic diseased liver samples at transplantation.Aim 2. To identify murine pro-inflammatory macrophage subsets that are re-programmed by FXR agonism in a model of reversible obstructive cholestasis. Our innovative study will be the first to use scRNA-seq to define macrophage heterogeneity among different diseases and overcomes a gap in knowledge on how disease-specific environmental cues drives pathologic macrophage polarization.