Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes
Abstract Hepatic encephalopathy (HE) is a common complication of liver cirrhosis, associated with high morbidity and mortality, for which no brain-targeted therapies exist at present. The interplay between hyperammonemia and inflammation is thought to drive HE development. As such, astrocytes, the m...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Journal of Neuroinflammation |
| Online Access: | https://doi.org/10.1186/s12974-023-02814-w |
| _version_ | 1797811352463474688 |
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| author | Wouter Claeys Lien Van Hoecke Hannah Lernout Clint De Nolf Griet Van Imschoot Elien Van Wonterghem Daan Verhaege Jonas Castelein Anja Geerts Christophe Van Steenkiste Roosmarijn E. Vandenbroucke |
| author_facet | Wouter Claeys Lien Van Hoecke Hannah Lernout Clint De Nolf Griet Van Imschoot Elien Van Wonterghem Daan Verhaege Jonas Castelein Anja Geerts Christophe Van Steenkiste Roosmarijn E. Vandenbroucke |
| author_sort | Wouter Claeys |
| collection | DOAJ |
| description | Abstract Hepatic encephalopathy (HE) is a common complication of liver cirrhosis, associated with high morbidity and mortality, for which no brain-targeted therapies exist at present. The interplay between hyperammonemia and inflammation is thought to drive HE development. As such, astrocytes, the most important ammonia-metabolizing cells in the brain, and microglia, the main immunomodulatory cells in the brain, have been heavily implicated in HE development. As insight into cellular perturbations driving brain pathology remains largely elusive, we aimed to investigate cell-type specific transcriptomic changes in the HE brain. In the recently established mouse bile duct ligation (BDL) model of HE, we performed RNA-Seq of sorted astrocytes and microglia at 14 and 28 days after induction. This revealed a marked transcriptional response in both cell types which was most pronounced in microglia. In both cell types, pathways related to inflammation and hypoxia, mechanisms commonly implicated in HE, were enriched. Additionally, astrocytes exhibited increased corticoid receptor and oxidative stress signaling, whereas microglial transcriptome changes were linked to immune cell attraction. Accordingly, both monocytes and neutrophils accumulated in the BDL mouse brain. Time-dependent changes were limited in both cell types, suggesting early establishment of a pathological phenotype. While HE is often considered a unique form of encephalopathy, astrocytic and microglial transcriptomes showed significant overlap with previously established gene expression signatures in other neuroinflammatory diseases like septic encephalopathy and stroke, suggesting common pathophysiological mechanisms. Our dataset identifies key molecular mechanisms involved in preclinical HE and provides a valuable resource for development of novel glial-directed therapeutic strategies. Graphical Abstract |
| first_indexed | 2024-03-13T07:22:26Z |
| format | Article |
| id | doaj.art-941f27bb31d8449898228eaff89de72f |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-13T07:22:26Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-941f27bb31d8449898228eaff89de72f2023-06-04T11:34:48ZengBMCJournal of Neuroinflammation1742-20942023-05-0120112010.1186/s12974-023-02814-wExperimental hepatic encephalopathy causes early but sustained glial transcriptional changesWouter Claeys0Lien Van Hoecke1Hannah Lernout2Clint De Nolf3Griet Van Imschoot4Elien Van Wonterghem5Daan Verhaege6Jonas Castelein7Anja Geerts8Christophe Van Steenkiste9Roosmarijn E. Vandenbroucke10Hepatology Research Unit, Department of Internal Medicine and Paediatrics, Ghent UniversityBarriers in Inflammation, VIB Center for Inflammation Research, VIBBarriers in Inflammation, VIB Center for Inflammation Research, VIBBarriers in Inflammation, VIB Center for Inflammation Research, VIBBarriers in Inflammation, VIB Center for Inflammation Research, VIBBarriers in Inflammation, VIB Center for Inflammation Research, VIBBarriers in Inflammation, VIB Center for Inflammation Research, VIBBarriers in Inflammation, VIB Center for Inflammation Research, VIBHepatology Research Unit, Department of Internal Medicine and Paediatrics, Ghent UniversityDepartment of Gastroenterology and Hepatology, Antwerp UniversityBarriers in Inflammation, VIB Center for Inflammation Research, VIBAbstract Hepatic encephalopathy (HE) is a common complication of liver cirrhosis, associated with high morbidity and mortality, for which no brain-targeted therapies exist at present. The interplay between hyperammonemia and inflammation is thought to drive HE development. As such, astrocytes, the most important ammonia-metabolizing cells in the brain, and microglia, the main immunomodulatory cells in the brain, have been heavily implicated in HE development. As insight into cellular perturbations driving brain pathology remains largely elusive, we aimed to investigate cell-type specific transcriptomic changes in the HE brain. In the recently established mouse bile duct ligation (BDL) model of HE, we performed RNA-Seq of sorted astrocytes and microglia at 14 and 28 days after induction. This revealed a marked transcriptional response in both cell types which was most pronounced in microglia. In both cell types, pathways related to inflammation and hypoxia, mechanisms commonly implicated in HE, were enriched. Additionally, astrocytes exhibited increased corticoid receptor and oxidative stress signaling, whereas microglial transcriptome changes were linked to immune cell attraction. Accordingly, both monocytes and neutrophils accumulated in the BDL mouse brain. Time-dependent changes were limited in both cell types, suggesting early establishment of a pathological phenotype. While HE is often considered a unique form of encephalopathy, astrocytic and microglial transcriptomes showed significant overlap with previously established gene expression signatures in other neuroinflammatory diseases like septic encephalopathy and stroke, suggesting common pathophysiological mechanisms. Our dataset identifies key molecular mechanisms involved in preclinical HE and provides a valuable resource for development of novel glial-directed therapeutic strategies. Graphical Abstracthttps://doi.org/10.1186/s12974-023-02814-w |
| spellingShingle | Wouter Claeys Lien Van Hoecke Hannah Lernout Clint De Nolf Griet Van Imschoot Elien Van Wonterghem Daan Verhaege Jonas Castelein Anja Geerts Christophe Van Steenkiste Roosmarijn E. Vandenbroucke Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes Journal of Neuroinflammation |
| title | Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes |
| title_full | Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes |
| title_fullStr | Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes |
| title_full_unstemmed | Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes |
| title_short | Experimental hepatic encephalopathy causes early but sustained glial transcriptional changes |
| title_sort | experimental hepatic encephalopathy causes early but sustained glial transcriptional changes |
| url | https://doi.org/10.1186/s12974-023-02814-w |
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