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Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells
Fulminant hepatitis (FH) is a life-threatening disease with partially understood pathogenesis. It has been demonstrated that myeloid-derived suppressor cells (MDSCs) are recruited into the liver during this process, and their augmented accumulation by various strategies protects against liver injury...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899575/ https://www.ncbi.nlm.nih.gov/pubmed/35265209 http://dx.doi.org/10.7150/thno.65916 |
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author | Liu, Genyu Wang, Qingyang Deng, Lijiao Huang, Xiaofeng Yang, Guang Cheng, Qianqian Guo, Tingting Guo, Lu Niu, Chunxiao Yang, Xiqin Dong, Jie Zhang, Jiyan |
author_facet | Liu, Genyu Wang, Qingyang Deng, Lijiao Huang, Xiaofeng Yang, Guang Cheng, Qianqian Guo, Tingting Guo, Lu Niu, Chunxiao Yang, Xiqin Dong, Jie Zhang, Jiyan |
author_sort | Liu, Genyu |
collection | PubMed |
description | Fulminant hepatitis (FH) is a life-threatening disease with partially understood pathogenesis. It has been demonstrated that myeloid-derived suppressor cells (MDSCs) are recruited into the liver during this process, and their augmented accumulation by various strategies protects against liver injury. However, the underlying mechanism(s) remain elusive. Receptor for activated C kinase 1 (RACK1), a multi-functional scaffold protein, is highly expressed in normal liver and has been implicated in liver physiology and diseases, but the in vivo role of hepatic RACK1 in FH remains unknown. Methods: Survival curves and liver damage were monitored to investigate the in vivo role of hepatic RACK1 in FH. The liver microenvironment was explored by microarray-based transcriptome analysis, flow cytometry, immunoblotting, and immunohistochemistry. MDSCs were identified with phenotypic and functional characteristics. Functional antibodies were used to target MDSCs. Co-culture techniques were used to study the underlying mechanism(s) of protection. The interaction of RACK1 with histone deacetylase 1 (HDAC1) and the consequent effects on HDAC1 ubiquitination were analyzed. Ectopic expression of HDAC1 with recombinant adeno-associated virus serotype 8 was conducted to confirm the role of HDAC1 in the protective effects of hepatic RACK1 deficiency against FH. Post-translational modifications of RACK1 were also investigated during the induction of FH. Results: Liver-specific RACK1 deficiency rendered mice resistant to FH. RACK1-deficient livers exhibited high basal levels of chemokine (C-X-C motif) ligand 1 (CXCL1) and S100 calcium-binding protein A9 (S100A9), associated with MDSC accumulation under steady-state conditions. Targeting MDSCs with an antibody against either Gr1 or DR5 abrogated the protective effects of liver-specific RACK1 deficiency. Accumulated MDSCs inhibited inflammatory cytokine production from macrophages and enhanced IκB kinase (IKK)/NF-κB pathway activation in hepatocytes. Further investigation revealed that RACK1 maintained HDAC1 protein level in hepatocytes by direct binding, thereby controlling histone H3K9 and H3K27 acetylation at the Cxcl1 and S100a9 promoters. Ectopic expression of HDAC1 in livers with RACK1 deficiency partially reversed the augmented Cxcl1/S100a9 → MDSCs → IKK/NF-κB axis. During FH induction, RACK1 was phosphorylated at serine 110, enhancing its binding to ubiquitin-conjugating enzyme E2T and promoting its ubiquitination and degradation. Conclusion: Liver-specific RACK1 deficiency protects against FH through accelerated HDAC1 degradation and the consequent CXCL1/S100A9 upregulation and MDSC accumulation. |
format | Online Article Text |
id | pubmed-8899575 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-88995752022-03-08 Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells Liu, Genyu Wang, Qingyang Deng, Lijiao Huang, Xiaofeng Yang, Guang Cheng, Qianqian Guo, Tingting Guo, Lu Niu, Chunxiao Yang, Xiqin Dong, Jie Zhang, Jiyan Theranostics Research Paper Fulminant hepatitis (FH) is a life-threatening disease with partially understood pathogenesis. It has been demonstrated that myeloid-derived suppressor cells (MDSCs) are recruited into the liver during this process, and their augmented accumulation by various strategies protects against liver injury. However, the underlying mechanism(s) remain elusive. Receptor for activated C kinase 1 (RACK1), a multi-functional scaffold protein, is highly expressed in normal liver and has been implicated in liver physiology and diseases, but the in vivo role of hepatic RACK1 in FH remains unknown. Methods: Survival curves and liver damage were monitored to investigate the in vivo role of hepatic RACK1 in FH. The liver microenvironment was explored by microarray-based transcriptome analysis, flow cytometry, immunoblotting, and immunohistochemistry. MDSCs were identified with phenotypic and functional characteristics. Functional antibodies were used to target MDSCs. Co-culture techniques were used to study the underlying mechanism(s) of protection. The interaction of RACK1 with histone deacetylase 1 (HDAC1) and the consequent effects on HDAC1 ubiquitination were analyzed. Ectopic expression of HDAC1 with recombinant adeno-associated virus serotype 8 was conducted to confirm the role of HDAC1 in the protective effects of hepatic RACK1 deficiency against FH. Post-translational modifications of RACK1 were also investigated during the induction of FH. Results: Liver-specific RACK1 deficiency rendered mice resistant to FH. RACK1-deficient livers exhibited high basal levels of chemokine (C-X-C motif) ligand 1 (CXCL1) and S100 calcium-binding protein A9 (S100A9), associated with MDSC accumulation under steady-state conditions. Targeting MDSCs with an antibody against either Gr1 or DR5 abrogated the protective effects of liver-specific RACK1 deficiency. Accumulated MDSCs inhibited inflammatory cytokine production from macrophages and enhanced IκB kinase (IKK)/NF-κB pathway activation in hepatocytes. Further investigation revealed that RACK1 maintained HDAC1 protein level in hepatocytes by direct binding, thereby controlling histone H3K9 and H3K27 acetylation at the Cxcl1 and S100a9 promoters. Ectopic expression of HDAC1 in livers with RACK1 deficiency partially reversed the augmented Cxcl1/S100a9 → MDSCs → IKK/NF-κB axis. During FH induction, RACK1 was phosphorylated at serine 110, enhancing its binding to ubiquitin-conjugating enzyme E2T and promoting its ubiquitination and degradation. Conclusion: Liver-specific RACK1 deficiency protects against FH through accelerated HDAC1 degradation and the consequent CXCL1/S100A9 upregulation and MDSC accumulation. Ivyspring International Publisher 2022-02-14 /pmc/articles/PMC8899575/ /pubmed/35265209 http://dx.doi.org/10.7150/thno.65916 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Liu, Genyu Wang, Qingyang Deng, Lijiao Huang, Xiaofeng Yang, Guang Cheng, Qianqian Guo, Tingting Guo, Lu Niu, Chunxiao Yang, Xiqin Dong, Jie Zhang, Jiyan Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells |
title | Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells |
title_full | Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells |
title_fullStr | Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells |
title_full_unstemmed | Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells |
title_short | Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells |
title_sort | hepatic rack1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899575/ https://www.ncbi.nlm.nih.gov/pubmed/35265209 http://dx.doi.org/10.7150/thno.65916 |
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