Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial CellsSUMMARY
Background & Aims: Congestion alters the microenvironment of the liver sinusoid along the portal-central axis. We studied spatial changes in immune cells in the sinusoid that contribute to congestive fibrosis and portal hypertension (PHTN). Methods: To visualize the distribution of immune ce...
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2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| author | Siyuan Ma Nawras W. Habash Mrunal K. Dehankar Nidhi Jalan-Sakrikar Shawna A. Cooper Abid A. Anwar Sofia Jerez Papawee Sutthirat Jinhang Gao Tamir Diamond Jing Jiao Caixin Qiu Jingchun Yang Sumera I. Ilyas Markcus Lee Usman Yaqoob Sheng Cao Rebecca G. Wells Vijay H. Shah Moira B. Hilscher |
| author_facet | Siyuan Ma Nawras W. Habash Mrunal K. Dehankar Nidhi Jalan-Sakrikar Shawna A. Cooper Abid A. Anwar Sofia Jerez Papawee Sutthirat Jinhang Gao Tamir Diamond Jing Jiao Caixin Qiu Jingchun Yang Sumera I. Ilyas Markcus Lee Usman Yaqoob Sheng Cao Rebecca G. Wells Vijay H. Shah Moira B. Hilscher |
| author_sort | Siyuan Ma |
| collection | DOAJ |
| description | Background & Aims: Congestion alters the microenvironment of the liver sinusoid along the portal-central axis. We studied spatial changes in immune cells in the sinusoid that contribute to congestive fibrosis and portal hypertension (PHTN). Methods: To visualize the distribution of immune cells in congestive hepatopathy (CH), we performed imaging mass cytometry (IMC) on liver tissue from patients with CH, Fontan-associated liver disease (FALD), and controls. We performed partial ligation of the inferior vena cava (pIVCL) to simulate CH in mice and isolated primary liver cells for single-cell RNA-sequencing (scRNA-seq) to study zonation of liver sinusoidal endothelial cells (LSECs). After pIVCL, mice were treated with intraperitoneal injections of AMG487, an inhibitor of the CXCL9 receptor, or a neutralizing antibody to CXCL9. Results: Intra-hepatic macrophages are enriched in CH and FALD. Given the role of CXCL9 in macrophage patterning in the liver, we performed RNA in situ hybridization (RNAish) in CH and determined that CXCL9 was highly expressed in LSECs in FALD, suggesting that LSECs recruit macrophages in CH. After pIVCL, treatment with AMG487 or an antibody to CXCL9 attenuated portal pressures, fibrosis, and intra-hepatic macrophages. To study changes in LSECs that promote macrophage chemotaxis, we performed scRNA-seq after pIVCL and sham procedures. Analysis revealed 3 LSEC subpopulations according to sinusoidal location. RNAish identified peri-central LSECs as the predominant source of CXCL9 in FALD. In vitro analyses revealed that β-catenin and hypoxia inducible factor-1 α regulate CXCL9 transcription in peri-central LSECs. Conclusions: CXCL9 derived from peri-central LSECs enriches intra-hepatic macrophages in CH and FALD, contributing to congestive fibrosis and PHTN. Strategies to target LSEC-derived CXCL9 may prevent the progression of CH and FALD. |
| format | Article |
| id | doaj-art-0edb19feca0d44eebc187d6ff49029ef |
| institution | OA Journals |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-0edb19feca0d44eebc187d6ff49029ef2025-08-20T02:24:58ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-0119710147510.1016/j.jcmgh.2025.101475Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial CellsSUMMARYSiyuan Ma0Nawras W. Habash1Mrunal K. Dehankar2Nidhi Jalan-Sakrikar3Shawna A. Cooper4Abid A. Anwar5Sofia Jerez6Papawee Sutthirat7Jinhang Gao8Tamir Diamond9Jing Jiao10Caixin Qiu11Jingchun Yang12Sumera I. Ilyas13Markcus Lee14Usman Yaqoob15Sheng Cao16Rebecca G. Wells17Vijay H. Shah18Moira B. Hilscher19Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TennesseeDivision of Gastroenterology and Hepatology, Children’s Hospital of Philadelphia, Philadelphia, PennsylvaniaDepartment of Bioinformatics, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaLaboratory of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, ChinaDivision of Gastroenterology and Hepatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, University of Pennsylvania, Philadelphia, PennsylvaniaDivision of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PennsylvaniaDepartment of Radiology, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PennsylvaniaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MinnesotaDivision of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Correspondence Address correspondence to: Moira B. Hilscher, MD, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905; tel: (507) 266-3760.Background & Aims: Congestion alters the microenvironment of the liver sinusoid along the portal-central axis. We studied spatial changes in immune cells in the sinusoid that contribute to congestive fibrosis and portal hypertension (PHTN). Methods: To visualize the distribution of immune cells in congestive hepatopathy (CH), we performed imaging mass cytometry (IMC) on liver tissue from patients with CH, Fontan-associated liver disease (FALD), and controls. We performed partial ligation of the inferior vena cava (pIVCL) to simulate CH in mice and isolated primary liver cells for single-cell RNA-sequencing (scRNA-seq) to study zonation of liver sinusoidal endothelial cells (LSECs). After pIVCL, mice were treated with intraperitoneal injections of AMG487, an inhibitor of the CXCL9 receptor, or a neutralizing antibody to CXCL9. Results: Intra-hepatic macrophages are enriched in CH and FALD. Given the role of CXCL9 in macrophage patterning in the liver, we performed RNA in situ hybridization (RNAish) in CH and determined that CXCL9 was highly expressed in LSECs in FALD, suggesting that LSECs recruit macrophages in CH. After pIVCL, treatment with AMG487 or an antibody to CXCL9 attenuated portal pressures, fibrosis, and intra-hepatic macrophages. To study changes in LSECs that promote macrophage chemotaxis, we performed scRNA-seq after pIVCL and sham procedures. Analysis revealed 3 LSEC subpopulations according to sinusoidal location. RNAish identified peri-central LSECs as the predominant source of CXCL9 in FALD. In vitro analyses revealed that β-catenin and hypoxia inducible factor-1 α regulate CXCL9 transcription in peri-central LSECs. Conclusions: CXCL9 derived from peri-central LSECs enriches intra-hepatic macrophages in CH and FALD, contributing to congestive fibrosis and PHTN. Strategies to target LSEC-derived CXCL9 may prevent the progression of CH and FALD.http://www.sciencedirect.com/science/article/pii/S2352345X25000165Fontan-associated Liver DiseaseFibrosisHypoxiaImaging Mass CytometryPortal Hypertension |
| spellingShingle | Siyuan Ma Nawras W. Habash Mrunal K. Dehankar Nidhi Jalan-Sakrikar Shawna A. Cooper Abid A. Anwar Sofia Jerez Papawee Sutthirat Jinhang Gao Tamir Diamond Jing Jiao Caixin Qiu Jingchun Yang Sumera I. Ilyas Markcus Lee Usman Yaqoob Sheng Cao Rebecca G. Wells Vijay H. Shah Moira B. Hilscher Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial CellsSUMMARY Cellular and Molecular Gastroenterology and Hepatology Fontan-associated Liver Disease Fibrosis Hypoxia Imaging Mass Cytometry Portal Hypertension |
| title | Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial CellsSUMMARY |
| title_full | Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial CellsSUMMARY |
| title_fullStr | Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial CellsSUMMARY |
| title_full_unstemmed | Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial CellsSUMMARY |
| title_short | Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial CellsSUMMARY |
| title_sort | congestion enriches intra hepatic macrophages through reverse zonation of cxcl9 in liver sinusoidal endothelial cellssummary |
| topic | Fontan-associated Liver Disease Fibrosis Hypoxia Imaging Mass Cytometry Portal Hypertension |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X25000165 |
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