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Efficiently Restored Thrombopoietin Production by Ashwell‐Morell Receptor and IL‐6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy
BACKGROUND AND AIMS: Thrombocytopenia has been described in most patients with acute and chronic liver failure. Decreased platelet production and decreased half‐life of platelets might be a consequence of low levels of thrombopoietin (TPO) in these patients. Platelet production is tightly regulated...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236498/ https://www.ncbi.nlm.nih.gov/pubmed/33369745 http://dx.doi.org/10.1002/hep.31698 |
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author | Reusswig, Friedrich Fazel Modares, Nastaran Brechtenkamp, Marius Wienands, Leonard Krüger, Irena Behnke, Kristina Lee‐Sundlov, Melissa M. Herebian, Diran Scheller, Jürgen Hoffmeister, Karin M. Häussinger, Dieter Elvers, Margitta |
author_facet | Reusswig, Friedrich Fazel Modares, Nastaran Brechtenkamp, Marius Wienands, Leonard Krüger, Irena Behnke, Kristina Lee‐Sundlov, Melissa M. Herebian, Diran Scheller, Jürgen Hoffmeister, Karin M. Häussinger, Dieter Elvers, Margitta |
author_sort | Reusswig, Friedrich |
collection | PubMed |
description | BACKGROUND AND AIMS: Thrombocytopenia has been described in most patients with acute and chronic liver failure. Decreased platelet production and decreased half‐life of platelets might be a consequence of low levels of thrombopoietin (TPO) in these patients. Platelet production is tightly regulated to avoid bleeding complications after vessel injury and can be enhanced under elevated platelet destruction as observed in liver disease. Thrombopoietin (TPO) is the primary regulator of platelet biogenesis and supports proliferation and differentiation of megakaryocytes. APPROACH AND RESULTS: Recent work provided evidence for the control of TPO mRNA expression in liver and bone marrow (BM) by scanning circulating platelets. The Ashwell‐Morell receptor (AMR) was identified to bind desialylated platelets to regulate hepatic thrombopoietin (TPO) production by Janus kinase (JAK2)/signal transducer and activator of transcription (STAT3) activation. Two‐thirds partial hepatectomy (PHx) was performed in mice. Platelet activation and clearance by AMR/JAK2/STAT3 signaling and TPO production were analyzed at different time points after PHx. Here, we demonstrate that PHx in mice led to thrombocytopenia and platelet activation defects leading to bleeding complications, but unaltered arterial thrombosis, in these mice. Platelet counts were rapidly restored by up‐regulation and crosstalk of the AMR and the IL‐6 receptor (IL‐6R) to induce JAK2‐STAT3‐TPO activation in the liver, accompanied by an increased number of megakaryocytes in spleen and BM before liver was completely regenerated. CONCLUSIONS: The AMR/IL‐6R‐STAT3‐TPO signaling pathway is an acute‐phase response to liver injury to reconstitute hemostasis. Bleeding complications were attributable to thrombocytopenia and platelet defects induced by elevated PGI(2), NO, and bile acid plasma levels early after PHx that might also be causative for the high mortality in patients with liver disease. |
format | Online Article Text |
id | pubmed-8236498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82364982021-07-28 Efficiently Restored Thrombopoietin Production by Ashwell‐Morell Receptor and IL‐6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy Reusswig, Friedrich Fazel Modares, Nastaran Brechtenkamp, Marius Wienands, Leonard Krüger, Irena Behnke, Kristina Lee‐Sundlov, Melissa M. Herebian, Diran Scheller, Jürgen Hoffmeister, Karin M. Häussinger, Dieter Elvers, Margitta Hepatology Original Articles BACKGROUND AND AIMS: Thrombocytopenia has been described in most patients with acute and chronic liver failure. Decreased platelet production and decreased half‐life of platelets might be a consequence of low levels of thrombopoietin (TPO) in these patients. Platelet production is tightly regulated to avoid bleeding complications after vessel injury and can be enhanced under elevated platelet destruction as observed in liver disease. Thrombopoietin (TPO) is the primary regulator of platelet biogenesis and supports proliferation and differentiation of megakaryocytes. APPROACH AND RESULTS: Recent work provided evidence for the control of TPO mRNA expression in liver and bone marrow (BM) by scanning circulating platelets. The Ashwell‐Morell receptor (AMR) was identified to bind desialylated platelets to regulate hepatic thrombopoietin (TPO) production by Janus kinase (JAK2)/signal transducer and activator of transcription (STAT3) activation. Two‐thirds partial hepatectomy (PHx) was performed in mice. Platelet activation and clearance by AMR/JAK2/STAT3 signaling and TPO production were analyzed at different time points after PHx. Here, we demonstrate that PHx in mice led to thrombocytopenia and platelet activation defects leading to bleeding complications, but unaltered arterial thrombosis, in these mice. Platelet counts were rapidly restored by up‐regulation and crosstalk of the AMR and the IL‐6 receptor (IL‐6R) to induce JAK2‐STAT3‐TPO activation in the liver, accompanied by an increased number of megakaryocytes in spleen and BM before liver was completely regenerated. CONCLUSIONS: The AMR/IL‐6R‐STAT3‐TPO signaling pathway is an acute‐phase response to liver injury to reconstitute hemostasis. Bleeding complications were attributable to thrombocytopenia and platelet defects induced by elevated PGI(2), NO, and bile acid plasma levels early after PHx that might also be causative for the high mortality in patients with liver disease. John Wiley and Sons Inc. 2021-06-04 2021-07 /pmc/articles/PMC8236498/ /pubmed/33369745 http://dx.doi.org/10.1002/hep.31698 Text en © 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Reusswig, Friedrich Fazel Modares, Nastaran Brechtenkamp, Marius Wienands, Leonard Krüger, Irena Behnke, Kristina Lee‐Sundlov, Melissa M. Herebian, Diran Scheller, Jürgen Hoffmeister, Karin M. Häussinger, Dieter Elvers, Margitta Efficiently Restored Thrombopoietin Production by Ashwell‐Morell Receptor and IL‐6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy |
title | Efficiently Restored Thrombopoietin Production by Ashwell‐Morell Receptor and IL‐6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy |
title_full | Efficiently Restored Thrombopoietin Production by Ashwell‐Morell Receptor and IL‐6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy |
title_fullStr | Efficiently Restored Thrombopoietin Production by Ashwell‐Morell Receptor and IL‐6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy |
title_full_unstemmed | Efficiently Restored Thrombopoietin Production by Ashwell‐Morell Receptor and IL‐6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy |
title_short | Efficiently Restored Thrombopoietin Production by Ashwell‐Morell Receptor and IL‐6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy |
title_sort | efficiently restored thrombopoietin production by ashwell‐morell receptor and il‐6r induced janus kinase 2/signal transducer and activator of transcription signaling early after partial hepatectomy |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236498/ https://www.ncbi.nlm.nih.gov/pubmed/33369745 http://dx.doi.org/10.1002/hep.31698 |
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