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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...

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Autores principales: Liu, Genyu, Wang, Qingyang, Deng, Lijiao, Huang, Xiaofeng, Yang, Guang, Cheng, Qianqian, Guo, Tingting, Guo, Lu, Niu, Chunxiao, Yang, Xiqin, Dong, Jie, Zhang, Jiyan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2022
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.
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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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