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Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis
Nucleotide‐binding oligomerization domain‐like receptor‐family pyrin domain‐containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL‐18 in hepatic stellate cells (HSCs)...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984672/ https://www.ncbi.nlm.nih.gov/pubmed/36059147 http://dx.doi.org/10.1002/hep.32776 |
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author | Knorr, Jana Kaufmann, Benedikt Inzaugarat, Maria Eugenia Holtmann, Theresa Maria Geisler, Lukas Hundertmark, Jana Kohlhepp, Marlene Sophia Boosheri, Laela M. Chilin‐Fuentes, Daisy R. Birmingham, Amanda Fisch, Kathleen M. Schilling, Joel D. Loosen, Sven H. Trautwein, Christian Roderburg, Christoph Demir, Münevver Tacke, Frank Hoffman, Hal M. Feldstein, Ariel E. Wree, Alexander |
author_facet | Knorr, Jana Kaufmann, Benedikt Inzaugarat, Maria Eugenia Holtmann, Theresa Maria Geisler, Lukas Hundertmark, Jana Kohlhepp, Marlene Sophia Boosheri, Laela M. Chilin‐Fuentes, Daisy R. Birmingham, Amanda Fisch, Kathleen M. Schilling, Joel D. Loosen, Sven H. Trautwein, Christian Roderburg, Christoph Demir, Münevver Tacke, Frank Hoffman, Hal M. Feldstein, Ariel E. Wree, Alexander |
author_sort | Knorr, Jana |
collection | PubMed |
description | Nucleotide‐binding oligomerization domain‐like receptor‐family pyrin domain‐containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL‐18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis. APPROACH AND RESULTS: We observed significantly increased serum levels of IL‐18 (128.4 pg/ml vs. 74.9 pg/ml) and IL‐18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1. Treatment of cultured primary murine HSC with recombinant mouse IL‐18 accelerated their transdifferentiation into myofibroblasts. In vivo, IL‐18 receptor‐deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC‐specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH‐induced fibrosis by feeding a choline‐deficient, L‐amino acid‐defined, high fat diet showed that genes related to IL‐18 and its downstream signaling were significantly upregulated, and Il18 ( −/− ) mice receiving this diet for 10 weeks showed protection from fibrotic changes with decreased number of alpha smooth muscle actin‐positive cells and collagen deposition. HSC activation triggered by NLRP3 inflammasome activation was abrogated when IL‐18 signaling was blocked by its naturally occurring antagonist IL‐18BP. Accordingly, we observed that the severe inflammatory phenotype associated with myeloid cell‐specific NLRP3 gain‐of‐function was rescued by IL‐18BP. CONCLUSIONS: Our study highlights the role of IL‐18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL‐18 as a target to treat liver fibrosis. |
format | Online Article Text |
id | pubmed-9984672 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-99846722023-05-17 Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis Knorr, Jana Kaufmann, Benedikt Inzaugarat, Maria Eugenia Holtmann, Theresa Maria Geisler, Lukas Hundertmark, Jana Kohlhepp, Marlene Sophia Boosheri, Laela M. Chilin‐Fuentes, Daisy R. Birmingham, Amanda Fisch, Kathleen M. Schilling, Joel D. Loosen, Sven H. Trautwein, Christian Roderburg, Christoph Demir, Münevver Tacke, Frank Hoffman, Hal M. Feldstein, Ariel E. Wree, Alexander Hepatology Original Articles: Liver Pathobiology Nucleotide‐binding oligomerization domain‐like receptor‐family pyrin domain‐containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL‐18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis. APPROACH AND RESULTS: We observed significantly increased serum levels of IL‐18 (128.4 pg/ml vs. 74.9 pg/ml) and IL‐18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1. Treatment of cultured primary murine HSC with recombinant mouse IL‐18 accelerated their transdifferentiation into myofibroblasts. In vivo, IL‐18 receptor‐deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC‐specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH‐induced fibrosis by feeding a choline‐deficient, L‐amino acid‐defined, high fat diet showed that genes related to IL‐18 and its downstream signaling were significantly upregulated, and Il18 ( −/− ) mice receiving this diet for 10 weeks showed protection from fibrotic changes with decreased number of alpha smooth muscle actin‐positive cells and collagen deposition. HSC activation triggered by NLRP3 inflammasome activation was abrogated when IL‐18 signaling was blocked by its naturally occurring antagonist IL‐18BP. Accordingly, we observed that the severe inflammatory phenotype associated with myeloid cell‐specific NLRP3 gain‐of‐function was rescued by IL‐18BP. CONCLUSIONS: Our study highlights the role of IL‐18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL‐18 as a target to treat liver fibrosis. Lippincott Williams & Wilkins 2023-06 2022-10-12 /pmc/articles/PMC9984672/ /pubmed/36059147 http://dx.doi.org/10.1002/hep.32776 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) |
spellingShingle | Original Articles: Liver Pathobiology Knorr, Jana Kaufmann, Benedikt Inzaugarat, Maria Eugenia Holtmann, Theresa Maria Geisler, Lukas Hundertmark, Jana Kohlhepp, Marlene Sophia Boosheri, Laela M. Chilin‐Fuentes, Daisy R. Birmingham, Amanda Fisch, Kathleen M. Schilling, Joel D. Loosen, Sven H. Trautwein, Christian Roderburg, Christoph Demir, Münevver Tacke, Frank Hoffman, Hal M. Feldstein, Ariel E. Wree, Alexander Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis |
title | Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis |
title_full | Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis |
title_fullStr | Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis |
title_full_unstemmed | Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis |
title_short | Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis |
title_sort | interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis |
topic | Original Articles: Liver Pathobiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984672/ https://www.ncbi.nlm.nih.gov/pubmed/36059147 http://dx.doi.org/10.1002/hep.32776 |
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