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M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis

Necroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like macrophages...

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Autores principales: Bai, Li, Kong, Ming, Duan, Zhongping, Liu, Shuang, Zheng, Sujun, Chen, Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814003/
https://www.ncbi.nlm.nih.gov/pubmed/33462187
http://dx.doi.org/10.1038/s41419-020-03378-w
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author Bai, Li
Kong, Ming
Duan, Zhongping
Liu, Shuang
Zheng, Sujun
Chen, Yu
author_facet Bai, Li
Kong, Ming
Duan, Zhongping
Liu, Shuang
Zheng, Sujun
Chen, Yu
author_sort Bai, Li
collection PubMed
description Necroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like macrophages in acute-on-chronic liver failure (ACLF) in vitro and in vivo, namely, M2-like macrophages protect hepatocytes against apoptosis. Herein, we integrated necroptosis, S100A9, and necroinflammation into this hepatoprotection, and hypothesized M2-like macrophages exert a hepatoprotective effect through inhibiting necroptosis-S100A9-necroinflammation axis. To testify this hypothesis, control mice were pre-treated with necroptosis or S100A9 inhibitors followed by D-GalN/LPS challenge. The extent of liver injury and M1/M2 macrophage activation was assessed. Necroptosis signaling and S100A9 expression were analysed and compared in control and fibrotic mice with or without acute insult. To document the pivotal role of M2-like macrophages in necroptosis and S100A9 inhibition, loss-of-function and gain-of-function experiments were performed. In addition, necroinflammation and its dependence on necroptosis and S100A9 were analysed. Moreover, the inhibitory effects of M2-like macrophages on necroinflammation were investigated in vivo and in vitro. We found that: firstly, the inhibition of necroptosis signaling and S100A9 expression alleviated D-GalN/LPS-induced hepatic damage, which was accompanied by M2-like macrophage activation; secondly, fibrosis inhibited necroptosis signaling and S100A9 expression, which could be attributed to M2-like macrophage activation; thirdly, S100A9 may function as a downstream player of necroptosis signaling; fourthly, fibrosis suppressed necroptosis- and S100A9-dependent necroinflammation; and finally, M2-like macrophages inhibited NLRP3 inflammasome activation and resultant necroinflammation via IL-10. Therefore, M2-like macrophages exert a beneficial hepatoprotection by inhibiting necroptosis-S100A9-necroinflammation axis in ACLF. Our findings provide novel insight for treating ACLF patients by specially targeting this signaling axis.
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spelling pubmed-78140032021-01-25 M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis Bai, Li Kong, Ming Duan, Zhongping Liu, Shuang Zheng, Sujun Chen, Yu Cell Death Dis Article Necroptosis has emerged as a novel and crucial player in acute and chronic liver diseases. Necroptotic cells lead to the release of DAMPs including S100A9, followed by the development of necroinflammation. We previously have documented the beneficial hepatoprotection conferred by M2-like macrophages in acute-on-chronic liver failure (ACLF) in vitro and in vivo, namely, M2-like macrophages protect hepatocytes against apoptosis. Herein, we integrated necroptosis, S100A9, and necroinflammation into this hepatoprotection, and hypothesized M2-like macrophages exert a hepatoprotective effect through inhibiting necroptosis-S100A9-necroinflammation axis. To testify this hypothesis, control mice were pre-treated with necroptosis or S100A9 inhibitors followed by D-GalN/LPS challenge. The extent of liver injury and M1/M2 macrophage activation was assessed. Necroptosis signaling and S100A9 expression were analysed and compared in control and fibrotic mice with or without acute insult. To document the pivotal role of M2-like macrophages in necroptosis and S100A9 inhibition, loss-of-function and gain-of-function experiments were performed. In addition, necroinflammation and its dependence on necroptosis and S100A9 were analysed. Moreover, the inhibitory effects of M2-like macrophages on necroinflammation were investigated in vivo and in vitro. We found that: firstly, the inhibition of necroptosis signaling and S100A9 expression alleviated D-GalN/LPS-induced hepatic damage, which was accompanied by M2-like macrophage activation; secondly, fibrosis inhibited necroptosis signaling and S100A9 expression, which could be attributed to M2-like macrophage activation; thirdly, S100A9 may function as a downstream player of necroptosis signaling; fourthly, fibrosis suppressed necroptosis- and S100A9-dependent necroinflammation; and finally, M2-like macrophages inhibited NLRP3 inflammasome activation and resultant necroinflammation via IL-10. Therefore, M2-like macrophages exert a beneficial hepatoprotection by inhibiting necroptosis-S100A9-necroinflammation axis in ACLF. Our findings provide novel insight for treating ACLF patients by specially targeting this signaling axis. Nature Publishing Group UK 2021-01-18 /pmc/articles/PMC7814003/ /pubmed/33462187 http://dx.doi.org/10.1038/s41419-020-03378-w Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Bai, Li
Kong, Ming
Duan, Zhongping
Liu, Shuang
Zheng, Sujun
Chen, Yu
M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis
title M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis
title_full M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis
title_fullStr M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis
title_full_unstemmed M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis
title_short M2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-S100A9-necroinflammation axis
title_sort m2-like macrophages exert hepatoprotection in acute-on-chronic liver failure through inhibiting necroptosis-s100a9-necroinflammation axis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814003/
https://www.ncbi.nlm.nih.gov/pubmed/33462187
http://dx.doi.org/10.1038/s41419-020-03378-w
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