Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functions
IntroductionMacrophages 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...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1506195/full |
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| author | Kyle D. Gromer Shang-Yang Chen Gaurav Gadhvi Liang Feng Colin Shearn Swati Antala Swati Antala Joshua B. Wechsler Carla M. Cuda Cara L. Mack Ronald J. Sokol William J. Janssen Richard M. Green Harris Perlman Deborah R. Winter Sarah A. Taylor Sarah A. Taylor |
| author_facet | Kyle D. Gromer Shang-Yang Chen Gaurav Gadhvi Liang Feng Colin Shearn Swati Antala Swati Antala Joshua B. Wechsler Carla M. Cuda Cara L. Mack Ronald J. Sokol William J. Janssen Richard M. Green Harris Perlman Deborah R. Winter Sarah A. Taylor Sarah A. Taylor |
| author_sort | Kyle D. Gromer |
| collection | DOAJ |
| description | IntroductionMacrophages 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.MethodsWe 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).ResultsLy6c+ 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.ConclusionsOur 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. |
| format | Article |
| id | doaj-art-952e402a9ff24d768992aed8d646960e |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-952e402a9ff24d768992aed8d646960e2025-01-30T06:22:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011610.3389/fimmu.2025.15061951506195Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functionsKyle D. Gromer0Shang-Yang Chen1Gaurav Gadhvi2Liang Feng3Colin Shearn4Swati Antala5Swati Antala6Joshua B. Wechsler7Carla M. Cuda8Cara L. Mack9Ronald J. Sokol10William J. Janssen11Richard M. Green12Harris Perlman13Deborah R. Winter14Sarah A. Taylor15Sarah A. Taylor16Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United StatesDepartment of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United StatesDepartment of Pediatrics, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United StatesDivision of Hepatology, Department of Pediatrics, Kravis Children’s Hospital at Mount Sinai, New York, NY, United StatesDepartment of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United StatesDepartment of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Pediatrics, Children’s Wisconsin, Milwaukee, WI, United StatesDepartment of Pediatrics, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United StatesDepartment of Medicine, National Jewish Health, Denver, CO, United StatesDepartment of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Medicine, Northwestern University, Chicago, IL, United StatesDepartment of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United StatesDepartment of Pediatrics, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United StatesIntroductionMacrophages 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.MethodsWe 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).ResultsLy6c+ 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.ConclusionsOur 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1506195/fullcholestasisobstructive cholangiopathypediatric liver diseaseinnate immunityhepatic macrophages |
| spellingShingle | Kyle D. Gromer Shang-Yang Chen Gaurav Gadhvi Liang Feng Colin Shearn Swati Antala Swati Antala Joshua B. Wechsler Carla M. Cuda Cara L. Mack Ronald J. Sokol William J. Janssen Richard M. Green Harris Perlman Deborah R. Winter Sarah A. Taylor Sarah A. Taylor Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functions Frontiers in Immunology cholestasis obstructive cholangiopathy pediatric liver disease innate immunity hepatic macrophages |
| title | Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functions |
| title_full | Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functions |
| title_fullStr | Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functions |
| title_full_unstemmed | Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functions |
| title_short | Transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset-specific macrophage functions |
| title_sort | transcriptional analysis of murine biliary atresia identifies macrophage heterogeneity and subset specific macrophage functions |
| topic | cholestasis obstructive cholangiopathy pediatric liver disease innate immunity hepatic macrophages |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1506195/full |
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