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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1506195

Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functions

Provisionally accepted
Kyle D Gromer Kyle D Gromer 1Shang-Yang Chen Shang-Yang Chen 2Gaurav Gadhvi Gaurav Gadhvi 2Liang Feng Liang Feng 1Colin Shearn Colin Shearn 3Swati Antala Swati Antala 1,4Joshua B Wechsler Joshua B Wechsler 1Carla Marie Cuda Carla Marie Cuda 2Cara Mack Cara Mack 5RONALD J SOKOL RONALD J SOKOL 6William J Janssen William J Janssen 7Richard Green Richard Green 2Harris Perlman Harris Perlman 2Deborah R. Winter Deborah R. Winter 2Sarah Taylor Sarah Taylor 6*
  • 1 Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
  • 2 Northwestern University, Evanston, Illinois, United States
  • 3 University of Colorado, Denver, Colorado, United States
  • 4 Mount Sinai Hospital, New York, New York, United States
  • 5 Children's Hospital of Wisconsin, Milwaukee, Wisconsin, United States
  • 6 Children's Hospital Colorado, Aurora, United States
  • 7 National Jewish Health (United States), Denver, Colorado, United States

The final, formatted version of the article will be published soon.

    Introduction: Macrophages play an important role in disease progression of pediatric cholestatic liver disease, particularly biliary atresia (BA); however, the restorative versus pathogenic role for precise macrophage subsets remains poorly defined. We aimed to distinguish the transcriptional profiles and roles of defined macrophage subset(s) in murine BA. Methods: We used multiparameter flow cytometry and RNA-sequencing analysis to profile recruited CD11bhiCD64+ hepatic macrophages by cell surface expression of MHCII and Ly6c in the Rhesus rotavirus (RRV)-induced murine model of BA versus saline controls. Modulation of macrophage numbers via intra-peritoneal injections of clodronate-loaded liposomes was performed to determine the association between macrophage numbers and histologic injury (Ishak score). Results: Ly6c+ macrophages demonstrated the greatest increase in numbers and percent of total macrophages in murine BA versus saline controls whereas MHCII+ macrophages decreased. Transcriptional changes in murine BA MHCII+ macrophages included reduced expression of the Kupffer cell gene signature, lower expression of genes involved in homeostatic processes, and increased expression of genes involved in inflammatory processes. Ly6c+ macrophages in murine BA showed increased expression for Hif1a and other genes involved in the cellular response to hypoxia. Among all subsets, the number of Ly6c+ macrophages exhibited the strongest correlation with severity of histologic liver injury by Ishak score. Conclusions: Our data identify specific pathways upregulated in Ly6c vs MHCII+ macrophage subsets in murine BA. Transcriptional similarities between murine BA and human cholestatic macrophages may enable translation of future mechanistic studies to new macrophage subset-specific therapies.

    Keywords: Cholestasis, obstructive cholangiopathy, pediatric liver disease, innate immunity, Hepatic macrophages

    Received: 04 Oct 2024; Accepted: 06 Jan 2025.

    Copyright: © 2025 Gromer, Chen, Gadhvi, Feng, Shearn, Antala, Wechsler, Cuda, Mack, SOKOL, Janssen, Green, Perlman, Winter and Taylor. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Sarah Taylor, Children's Hospital Colorado, Aurora, United States

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