Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH
Background:. Immune cell–driven inflammation is a key mediator of metabolic dysfunction–associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulatio...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Health/LWW
2025-02-01
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| Series: | Hepatology Communications |
| Online Access: | http://journals.lww.com/10.1097/HC9.0000000000000613 |
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| author | Gopanandan Parthasarathy Nanditha Venkatesan Guneet Singh Sidhu Myeong Jun Song Chieh-Yu Liao Fanta Barrow Amy Mauer Tejasav Sehrawat Yasuhiko Nakao P. Vineeth Daniel Debanjali Dasgupta Kevin Pavelko Xavier S. Revelo Harmeet Malhi |
| author_facet | Gopanandan Parthasarathy Nanditha Venkatesan Guneet Singh Sidhu Myeong Jun Song Chieh-Yu Liao Fanta Barrow Amy Mauer Tejasav Sehrawat Yasuhiko Nakao P. Vineeth Daniel Debanjali Dasgupta Kevin Pavelko Xavier S. Revelo Harmeet Malhi |
| author_sort | Gopanandan Parthasarathy |
| collection | DOAJ |
| description | Background:. Immune cell–driven inflammation is a key mediator of metabolic dysfunction–associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T-cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages in the liver.
Methods:. The LyzMCre approach was used to generate myeloid cell–specific knockout mice, termed S1pr1
MKO
. Littermate S1pr1
loxp/loxp
mice were used as wild-type controls. MASH was established by feeding mice a high-fat, -fructose, and -cholesterol (FFC) diet for 24 weeks, which led to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry.
Results:. Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in high-fat, -fructose, and -cholesterol–fed S1pr1
MKO
compared to wild-type. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of high-fat, -fructose, and -cholesterol–fed S1pr1
MKO
mice compared to wild-type. Gene ontology pathway analysis revealed significant suppression of the peroxisome proliferator–activated receptor gamma and mitogen-activated protein kinase pathways in S1pr1
MKO
consistent with attenuated MASH in mice.
Conclusions:. Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH. |
| format | Article |
| id | doaj-art-f6c024a9745b4f629c23045ecd8d9382 |
| institution | Kabale University |
| issn | 2471-254X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj-art-f6c024a9745b4f629c23045ecd8d93822025-02-05T02:10:59ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2025-02-019210.1097/HC9.0000000000000613HC90000000000000613Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASHGopanandan Parthasarathy0Nanditha Venkatesan1Guneet Singh Sidhu2Myeong Jun Song3Chieh-Yu Liao4Fanta Barrow5Amy Mauer6Tejasav Sehrawat7Yasuhiko Nakao8P. Vineeth Daniel9Debanjali Dasgupta10Kevin Pavelko11Xavier S. Revelo12Harmeet Malhi13 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 3 Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA 5 Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA 3 Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA 1 Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USABackground:. Immune cell–driven inflammation is a key mediator of metabolic dysfunction–associated steatohepatitis (MASH) progression. We have previously demonstrated that pharmacological sphingosine 1-phosphate (S1P) receptor modulation ameliorates MASH and is associated with attenuated accumulation of intrahepatic macrophage and T-cell subsets. Although S1P receptors are expressed on several immune cell types, given the prominent role of monocyte-derived recruited macrophages in the sterile inflammation of MASH, we hypothesized that deletion of S1P receptor 1 (S1P1) on myeloid cells may ameliorate MASH by reducing the accumulation of proinflammatory monocyte-derived macrophages in the liver. Methods:. The LyzMCre approach was used to generate myeloid cell–specific knockout mice, termed S1pr1 MKO . Littermate S1pr1 loxp/loxp mice were used as wild-type controls. MASH was established by feeding mice a high-fat, -fructose, and -cholesterol (FFC) diet for 24 weeks, which led to the development of steatohepatitis and MASH-defining cardiometabolic risk factors. Liver injury and inflammation were determined by histological and gene expression analyses. Intrahepatic leukocyte populations were analyzed by mass cytometry and immunohistochemistry. Results:. Histological examination demonstrated a reduction in liver inflammatory infiltrates and fibrosis in high-fat, -fructose, and -cholesterol–fed S1pr1 MKO compared to wild-type. There was a corresponding reduction in alanine aminotransferase, a sensitive marker for liver injury. As determined by mass cytometry, a significant decrease in recruited macrophages was noted in the livers of high-fat, -fructose, and -cholesterol–fed S1pr1 MKO mice compared to wild-type. Gene ontology pathway analysis revealed significant suppression of the peroxisome proliferator–activated receptor gamma and mitogen-activated protein kinase pathways in S1pr1 MKO consistent with attenuated MASH in mice. Conclusions:. Deletion of S1P1 in myeloid cells is sufficient to attenuate intrahepatic accumulation of monocyte-derived macrophages and ameliorate murine MASH.http://journals.lww.com/10.1097/HC9.0000000000000613 |
| spellingShingle | Gopanandan Parthasarathy Nanditha Venkatesan Guneet Singh Sidhu Myeong Jun Song Chieh-Yu Liao Fanta Barrow Amy Mauer Tejasav Sehrawat Yasuhiko Nakao P. Vineeth Daniel Debanjali Dasgupta Kevin Pavelko Xavier S. Revelo Harmeet Malhi Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH Hepatology Communications |
| title | Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH |
| title_full | Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH |
| title_fullStr | Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH |
| title_full_unstemmed | Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH |
| title_short | Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH |
| title_sort | deletion of sphingosine 1 phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates mash |
| url | http://journals.lww.com/10.1097/HC9.0000000000000613 |
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