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 injury1-5, cell-specific immunotherapies have not been developed. We have been the first to perform single-cell RNA sequencing (scRNA-seq) on hepatic immune cell populations from patients with disease. We identified 3 distinct pro-inflammatory macrophage populations including a small RORA+ macrophage population at the interface between cholestatic and normal macrophage subsets6 on temporal trajectory analysis. RORA encodes retinoic acid receptor-related orphan receptor alpha (ROR) which is known to promote anti-inflammatory polarization of human macrophages7, regulate the hepatic acute phase response8, and protect against inflammation in nonalcoholic steatohepatitis9. Moreover, only low expression of RORA was present in non-diseased human macrophages6 suggesting this population may emerge in response to tissue injury and be a novel target to promote anti-inflammatory macrophage subsets. While treatment with the bile acid analogue farnesoid X receptor (FXR) agonist, a member of the nuclear receptor superfamily, has recently demonstrated a biochemical response in primary biliary cholangitis and primary sclerosing cholangitis10, 11, there has been no medical therapy shown to improve outcome. While FXR activation has been associated with suppression of the macrophage inflammasome, we and others have shown a lack of gene expression for NR1H4 encoding FXR in human and murine hepatic macrophages6, 12 demonstrating that this current therapy does not regulate the immune pathways in obstructive cholestasis. We will overcome this gap in knowledge and target ROR in an innovative murine model of reversible bile duct ligation (BDL/BDLR) that mimics hepatic injury and regeneration. With this model we will define the immune modulatory mechanism by which ROR agonism reprograms macrophages towards their natural reparative phenotype. We hypothesize that pathogenic pro-inflammatory macrophage subsets promote cholestatic injury due to insufficient regulation by RORA+ macrophages; ROR agonism will increase the critical anti-inflammatory RORA macrophage subset and reduce pathogenic populations.
|Effective start/end date||6/1/20 → 5/31/22|
- Ann & Robert H. Lurie Children's Hospital of Chicago (901605-NU (Winter)//1R21AI153747-01)
- National Institute of Allergy and Infectious Diseases (901605-NU (Winter)//1R21AI153747-01)
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