# Immune Modulation of Macrophages in Obstructive Cholestasis

> **NIH NIH R21** · LURIE CHILDREN'S HOSPITAL OF CHICAGO · 2020 · $244,191

## Abstract

PROJECT SUMMARY:
Obstructive cholestatic liver diseases carry a high medical burden as there is no medical therapy to prevent
disease progression and thus they remain a leading indication for liver transplantation. While the initial target in
obstructive cholangiopathies is the bile duct, the immune response is the major cause for ongoing liver injury.
Macrophages are known to play a significant role in the mechanism of cholestatic liver injury, however, disease-
modulating immunotherapies have not been established and represent an unmet medical need. We have been
the first to perform single-cell RNA sequencing (scRNA-seq) on cholestatic liver samples and will use this
preliminary data in the current study to overcome the gap in medical therapy.
We have identified a subset of RORA-expressing macrophages in cholestatic liver samples that is at the interface
between cholestatic and normal macrophages on pseudotime trajectory analysis. RORA encodes a retinoic acid
receptor-related orphan receptor alpha (ROR) that is known to promote anti-inflammatory polarization of human
macrophages. Our data suggests that RORA+ macrophages may emerge in cholestatic liver injury and thus be
a novel therapeutic target. While ROR-agonism has shown improvement in hepatic injury in a murine model
of non-alcoholic steatohepatitis, the role of RORA in cholestatic liver disease has not been investigated. We
hypothesize that RORA+ hepatic macrophages are necessary for the reparative response after
cholestatic injury; thus, ROR agonism will promote repair through the conversion of pro-inflammatory
macrophages into this critical pro-restorative subset.
We will investigate our hypothesis through: 1) correlation between clinical parameters of liver injury and the
transcriptional prolife of RORA+ hepatic macrophages in cholestatic and non-cholestatic human liver diseases
using scRNA-seq, 2) identification of the reparative macrophage immune response after alleviation of biliary
obstruction using an innovative murine model of reversible bile duct ligation, and 3) evaluation of changes in
disease phenotype in our murine model upon ROR-agonism. Transcriptional correlation between human and
murine macrophage subsets will provide the foundation to translate findings from the current study into future
human immune-modulatory therapeutic trials. In addition, data obtained from this proposal will enable further
studies on ROR-agonism in disease-specific murine models of cholestasis as well as fate-mapping experiments
to determine the origin (bone-marrow derived versus tissue-resident) of the ROR-responsive macrophages.

## Key facts

- **NIH application ID:** 10040905
- **Project number:** 1R21AI153747-01
- **Recipient organization:** LURIE CHILDREN'S HOSPITAL OF CHICAGO
- **Principal Investigator:** Sarah Ann Taylor
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $244,191
- **Award type:** 1
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10040905

## Citation

> US National Institutes of Health, RePORTER application 10040905, Immune Modulation of Macrophages in Obstructive Cholestasis (1R21AI153747-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10040905. Licensed CC0.

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