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C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis

C-X-C motif chemokine 10 (CXCL10) is a crucial pro-inflammatory factor in chronic hepatitis. Autophagy dysregulation is known to contribute to hepatic inflammatory injury. Hence, we investigated the regulatory effect of CXCL10 on the autophagosome-lysosome system during non-alcoholic fatty liver dis...

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Autores principales: Zhang, Xiang, Wu, William KK, Xu, Weiqi, Man, Kwan, Wang, Xiaojuan, Han, Juqiang, Leung, Wing Yan, Wu, Ruonan, Liu, Ken, Yu, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562218/
https://www.ncbi.nlm.nih.gov/pubmed/28824718
http://dx.doi.org/10.7150/thno.19068
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author Zhang, Xiang
Wu, William KK
Xu, Weiqi
Man, Kwan
Wang, Xiaojuan
Han, Juqiang
Leung, Wing Yan
Wu, Ruonan
Liu, Ken
Yu, Jun
author_facet Zhang, Xiang
Wu, William KK
Xu, Weiqi
Man, Kwan
Wang, Xiaojuan
Han, Juqiang
Leung, Wing Yan
Wu, Ruonan
Liu, Ken
Yu, Jun
author_sort Zhang, Xiang
collection PubMed
description C-X-C motif chemokine 10 (CXCL10) is a crucial pro-inflammatory factor in chronic hepatitis. Autophagy dysregulation is known to contribute to hepatic inflammatory injury. Hence, we investigated the regulatory effect of CXCL10 on the autophagosome-lysosome system during non-alcoholic fatty liver disease (NAFLD) development. The effect of CXCL10 ablation by neutralizing monoclonal antibody (mAb) or genetic knockout on autophagic flux was evaluated in cultured hepatocytes and animal models of NAFLD. Results demonstrated that CXCL10 ablation protected against hepatocyte injury in vitro and steatohepatitis development in mice. Autophagic flux impairment was rectified by CXCL10 inhibition using anti-CXCL10 mAb in AML-12 and HepG2 liver cell lines and primary hepatocytes as evidenced by the attenuated accumulation of p62/SQSTM1 and LC3-II proteins and increased autophagic protein degradation. Impaired autophagic flux was significantly restored by CXCL10 knockout or anti-CXCL10 mAb in mice. Bafilomycin A1, an inhibitor of autolysosome formation, abolished the rectifying effect of anti-CXCL10 mAb or CXCL10 knockdown in AML-12 and primary hepatocytes, indicating CXCL10 impaired late-stage autophagy in NAFLD. Anti-CXCL10 mAb treatment also increased the fusion of LC3-positive autophagosomes with lysosomes in HepG2 cells challenged with palmitic acid, suggesting that CXCL10 ablation restored autolysosome formation. Consistently, the number of autolysosomes was significantly increased by CXCL10 knockout in mice as shown by electron microscopy. In conclusion, upregulated CXCL10 in steatohepatitis impairs autophagic flux by reducing autolysosome formation, thereby inhibiting autophagic protein degradation and the accumulation of ubiquitinated proteins, leading to the development of steatohepatitis.
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spelling pubmed-55622182017-08-18 C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis Zhang, Xiang Wu, William KK Xu, Weiqi Man, Kwan Wang, Xiaojuan Han, Juqiang Leung, Wing Yan Wu, Ruonan Liu, Ken Yu, Jun Theranostics Research Paper C-X-C motif chemokine 10 (CXCL10) is a crucial pro-inflammatory factor in chronic hepatitis. Autophagy dysregulation is known to contribute to hepatic inflammatory injury. Hence, we investigated the regulatory effect of CXCL10 on the autophagosome-lysosome system during non-alcoholic fatty liver disease (NAFLD) development. The effect of CXCL10 ablation by neutralizing monoclonal antibody (mAb) or genetic knockout on autophagic flux was evaluated in cultured hepatocytes and animal models of NAFLD. Results demonstrated that CXCL10 ablation protected against hepatocyte injury in vitro and steatohepatitis development in mice. Autophagic flux impairment was rectified by CXCL10 inhibition using anti-CXCL10 mAb in AML-12 and HepG2 liver cell lines and primary hepatocytes as evidenced by the attenuated accumulation of p62/SQSTM1 and LC3-II proteins and increased autophagic protein degradation. Impaired autophagic flux was significantly restored by CXCL10 knockout or anti-CXCL10 mAb in mice. Bafilomycin A1, an inhibitor of autolysosome formation, abolished the rectifying effect of anti-CXCL10 mAb or CXCL10 knockdown in AML-12 and primary hepatocytes, indicating CXCL10 impaired late-stage autophagy in NAFLD. Anti-CXCL10 mAb treatment also increased the fusion of LC3-positive autophagosomes with lysosomes in HepG2 cells challenged with palmitic acid, suggesting that CXCL10 ablation restored autolysosome formation. Consistently, the number of autolysosomes was significantly increased by CXCL10 knockout in mice as shown by electron microscopy. In conclusion, upregulated CXCL10 in steatohepatitis impairs autophagic flux by reducing autolysosome formation, thereby inhibiting autophagic protein degradation and the accumulation of ubiquitinated proteins, leading to the development of steatohepatitis. Ivyspring International Publisher 2017-07-08 /pmc/articles/PMC5562218/ /pubmed/28824718 http://dx.doi.org/10.7150/thno.19068 Text en © Ivyspring International Publisher This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Zhang, Xiang
Wu, William KK
Xu, Weiqi
Man, Kwan
Wang, Xiaojuan
Han, Juqiang
Leung, Wing Yan
Wu, Ruonan
Liu, Ken
Yu, Jun
C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis
title C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis
title_full C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis
title_fullStr C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis
title_full_unstemmed C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis
title_short C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis
title_sort c-x-c motif chemokine 10 impairs autophagy and autolysosome formation in non-alcoholic steatohepatitis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562218/
https://www.ncbi.nlm.nih.gov/pubmed/28824718
http://dx.doi.org/10.7150/thno.19068
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