Journal
PLOS ONE
Volume 16, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0244743
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Funding
- George Ferry Young Investigator Award from the North American Society for Pediatric, Gastroenterology, Hepatology and Nutrition
- Pediatric Liver Research Fund, Lurie Children's Hospital Foundation, Chicago IL
- Northwestern Medicine Transplant Endowment Grant, Comprehensive Transplant Center, Northwestern Medicine, Chicago, IL
- NIH/NIAID [1R21AI153747-01, U19AI135964]
- American Lung Association
- Arthritis National Research Foundation
- American Thoracic Society
- Scleroderma Foundation
- American Federation for Aging Research
- American Heart Association [18CDA34110224]
- Northwestern University Flow Cytometry, Pathology, Immunotherapy Assessment Core, and Sequencing Core Facilities
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This study identified three distinct macrophage populations in pediatric cholestatic liver disease through single-cell RNA sequencing and immunofluorescence, characterized by their transcriptional profiles as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages. These cholestatic macrophages showed reduced expression of immune regulatory genes compared to normal hepatic macrophages, indicating potential for targeted therapeutic strategies in reducing cholestatic liver injury.
Background & aims Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease. Methods We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages. Results We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver. Conclusions We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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