Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis
Background and AimsPrimary Biliary Cholangitis (PBC) is an organ-specific autoimmune liver disease. Mononuclear phagocytes (MNPs), comprise of monocyte, dendritic cells and monocyte-derived macrophages, constitute major arm of the innate immune system known to be involved in the pathogenesis of auto...
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| Format: | Article |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.718841/full |
| _version_ | 1819153485977878528 |
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| author | Debby Reuveni Debby Reuveni Miriam R. Brezis Miriam R. Brezis Eli Brazowski Eli Brazowski Philip Vinestock Patrick S. C. Leung Paresh Thakker M. Eric Gershwin Ehud Zigmond Ehud Zigmond Ehud Zigmond |
| author_facet | Debby Reuveni Debby Reuveni Miriam R. Brezis Miriam R. Brezis Eli Brazowski Eli Brazowski Philip Vinestock Patrick S. C. Leung Paresh Thakker M. Eric Gershwin Ehud Zigmond Ehud Zigmond Ehud Zigmond |
| author_sort | Debby Reuveni |
| collection | DOAJ |
| description | Background and AimsPrimary Biliary Cholangitis (PBC) is an organ-specific autoimmune liver disease. Mononuclear phagocytes (MNPs), comprise of monocyte, dendritic cells and monocyte-derived macrophages, constitute major arm of the innate immune system known to be involved in the pathogenesis of autoimmune disorders. MNPs were shown to accumulate around intra-hepatic bile ducts in livers of PBC patients. Interleukin 23 (IL-23) is a pro-inflammatory cytokine. IL-23-positive cells were detected in livers of patients with advanced stage PBC and IL-23 serum levels found to be in correlation with PBC disease severity. Our overall goal was to assess the importance of IL-23 derived from MNPs in PBC pathogenesis.MethodsWe utilized an inducible murine model of PBC and took advantage of transgenic mice targeting expression of IL-23 by specific MNP populations. Analysis included liver histology assessment, flow cytometry of hepatic immune cells and hepatic cytokine profile evaluation. Specific MNPs sub-populations were sorted and assessed for IL-23 expression levels.ResultsFlow cytometry analysis of non-parenchymal liver cells in autoimmune cholangitis revealed massive infiltration of the liver by MNPs and neutrophils and a decrease in Kupffer cells numbers. In addition, a 4-fold increase in the incidence of hepatic IL-17A producing CD4+ T cells was found to be associated with an increase in hepatic IL23-p19 and IL17A expression levels. Disease severity was significantly ameliorated in both CD11ccreP19flox/flox and CX3CR1creP19 flox/flox mice as assessed by reduced portal inflammation and decreased hepatic expression of various inflammatory cytokines. Amelioration of disease severity was associated with reduction in IL-17A producing CD4+ T cells percentages and decreased hepatic IL23-p19 and IL17A expression levels. qRT-PCR analysis of sorted hepatic MNPs demonstrated high expression levels of IL-23 mRNA specifically by CX3CR1hiCD11c+ monocyte-derived macrophages.ConclusionOur results indicate a major role for IL-23 produced by hepatic monocyte-derived macrophages in the pathogenesis of PBC. These results may pave the road for the development of new immune-based and cell specific therapeutic modalities for PBC patients not responding to current therapies. |
| first_indexed | 2024-12-22T15:05:57Z |
| format | Article |
| id | doaj.art-5c60aa8d7f924c638f306b32c029dc2d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T15:05:57Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5c60aa8d7f924c638f306b32c029dc2d2022-12-21T18:22:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-08-011210.3389/fimmu.2021.718841718841Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary CholangitisDebby Reuveni0Debby Reuveni1Miriam R. Brezis2Miriam R. Brezis3Eli Brazowski4Eli Brazowski5Philip Vinestock6Patrick S. C. Leung7Paresh Thakker8M. Eric Gershwin9Ehud Zigmond10Ehud Zigmond11Ehud Zigmond12The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelThe Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelDivision of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United StatesRegeneron Pharmaceuticals, Inc., Tarrytown, NY, United StatesDivision of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA, United StatesThe Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelCenter for Autoimmune Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelBackground and AimsPrimary Biliary Cholangitis (PBC) is an organ-specific autoimmune liver disease. Mononuclear phagocytes (MNPs), comprise of monocyte, dendritic cells and monocyte-derived macrophages, constitute major arm of the innate immune system known to be involved in the pathogenesis of autoimmune disorders. MNPs were shown to accumulate around intra-hepatic bile ducts in livers of PBC patients. Interleukin 23 (IL-23) is a pro-inflammatory cytokine. IL-23-positive cells were detected in livers of patients with advanced stage PBC and IL-23 serum levels found to be in correlation with PBC disease severity. Our overall goal was to assess the importance of IL-23 derived from MNPs in PBC pathogenesis.MethodsWe utilized an inducible murine model of PBC and took advantage of transgenic mice targeting expression of IL-23 by specific MNP populations. Analysis included liver histology assessment, flow cytometry of hepatic immune cells and hepatic cytokine profile evaluation. Specific MNPs sub-populations were sorted and assessed for IL-23 expression levels.ResultsFlow cytometry analysis of non-parenchymal liver cells in autoimmune cholangitis revealed massive infiltration of the liver by MNPs and neutrophils and a decrease in Kupffer cells numbers. In addition, a 4-fold increase in the incidence of hepatic IL-17A producing CD4+ T cells was found to be associated with an increase in hepatic IL23-p19 and IL17A expression levels. Disease severity was significantly ameliorated in both CD11ccreP19flox/flox and CX3CR1creP19 flox/flox mice as assessed by reduced portal inflammation and decreased hepatic expression of various inflammatory cytokines. Amelioration of disease severity was associated with reduction in IL-17A producing CD4+ T cells percentages and decreased hepatic IL23-p19 and IL17A expression levels. qRT-PCR analysis of sorted hepatic MNPs demonstrated high expression levels of IL-23 mRNA specifically by CX3CR1hiCD11c+ monocyte-derived macrophages.ConclusionOur results indicate a major role for IL-23 produced by hepatic monocyte-derived macrophages in the pathogenesis of PBC. These results may pave the road for the development of new immune-based and cell specific therapeutic modalities for PBC patients not responding to current therapies.https://www.frontiersin.org/articles/10.3389/fimmu.2021.718841/fullprimary biliary cholangitismonocytesmacrophagescytokinesinterleukin-23 |
| spellingShingle | Debby Reuveni Debby Reuveni Miriam R. Brezis Miriam R. Brezis Eli Brazowski Eli Brazowski Philip Vinestock Patrick S. C. Leung Paresh Thakker M. Eric Gershwin Ehud Zigmond Ehud Zigmond Ehud Zigmond Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis Frontiers in Immunology primary biliary cholangitis monocytes macrophages cytokines interleukin-23 |
| title | Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis |
| title_full | Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis |
| title_fullStr | Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis |
| title_full_unstemmed | Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis |
| title_short | Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis |
| title_sort | interleukin 23 produced by hepatic monocyte derived macrophages is essential for the development of murine primary biliary cholangitis |
| topic | primary biliary cholangitis monocytes macrophages cytokines interleukin-23 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.718841/full |
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