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Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages

Although aggravated liver injury has been reported in aged livers post‐ischemia and reperfusion (IR), the underlying mechanism of innate immune activation of aged macrophages is not well understood. Here, we investigated whether and how Stimulator of interferon genes (STING) signaling regulated macr...

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Autores principales: Zhong, Weizhe, Rao, Zhuqing, Rao, Jianhua, Han, Guoyong, Wang, Ping, Jiang, Tao, Pan, Xiongxiong, Zhou, Shun, Zhou, Haoming, Wang, Xuehao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431827/
https://www.ncbi.nlm.nih.gov/pubmed/32666684
http://dx.doi.org/10.1111/acel.13186
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author Zhong, Weizhe
Rao, Zhuqing
Rao, Jianhua
Han, Guoyong
Wang, Ping
Jiang, Tao
Pan, Xiongxiong
Zhou, Shun
Zhou, Haoming
Wang, Xuehao
author_facet Zhong, Weizhe
Rao, Zhuqing
Rao, Jianhua
Han, Guoyong
Wang, Ping
Jiang, Tao
Pan, Xiongxiong
Zhou, Shun
Zhou, Haoming
Wang, Xuehao
author_sort Zhong, Weizhe
collection PubMed
description Although aggravated liver injury has been reported in aged livers post‐ischemia and reperfusion (IR), the underlying mechanism of innate immune activation of aged macrophages is not well understood. Here, we investigated whether and how Stimulator of interferon genes (STING) signaling regulated macrophage proinflammatory activation and liver IR injury. Mice were subjected to hepatic IR in vivo. Macrophages isolated from IR‐stressed livers and bone marrow‐derived macrophages (BMDMs) from young and aged mice were used for in vitro studies. Enhanced nucleotide‐binding domain and leucine‐rich repeat containing protein 3 (NLRP3) activation was found in both livers and macrophages of aged mice post‐IR. NLRP3 knockdown in macrophages inhibited intrahepatic inflammation and liver injury in both young and aged mice. Interestingly, enhanced activation of the STING/ TANK‐binding kinase 1 (TBK1) signaling pathway was observed in aged macrophages post‐IR and mitochondria DNA (mtDNA) stimulation. STING suppression blocked over‐activation of NLRP3 signaling and excessive secretion of proinflammatory cytokines/chemokines in the mtDNA‐stimulated BMDMs from aged mice. More importantly, STING knockdown in macrophages abrogated the detrimental role of aging in aggravating liver IR injury and intrahepatic inflammation. Finally, peripheral blood from the recipients undergoing liver transplantation was collected and analyzed. The results showed that the elderly recipients had much higher levels of TNF‐α, IL‐6, IL‐1β, and IL‐18 post‐transplantation, indicating increased NLRP3 activation in lR‐stressed livers of elderly recipients. In summary, our study demonstrated that the STING‐NLRP3 axis was critical for the proinflammatory response of aged macrophages and would be a novel therapeutic target to reduce IR injury in elderly patients.
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spelling pubmed-74318272020-08-20 Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages Zhong, Weizhe Rao, Zhuqing Rao, Jianhua Han, Guoyong Wang, Ping Jiang, Tao Pan, Xiongxiong Zhou, Shun Zhou, Haoming Wang, Xuehao Aging Cell Original Articles Although aggravated liver injury has been reported in aged livers post‐ischemia and reperfusion (IR), the underlying mechanism of innate immune activation of aged macrophages is not well understood. Here, we investigated whether and how Stimulator of interferon genes (STING) signaling regulated macrophage proinflammatory activation and liver IR injury. Mice were subjected to hepatic IR in vivo. Macrophages isolated from IR‐stressed livers and bone marrow‐derived macrophages (BMDMs) from young and aged mice were used for in vitro studies. Enhanced nucleotide‐binding domain and leucine‐rich repeat containing protein 3 (NLRP3) activation was found in both livers and macrophages of aged mice post‐IR. NLRP3 knockdown in macrophages inhibited intrahepatic inflammation and liver injury in both young and aged mice. Interestingly, enhanced activation of the STING/ TANK‐binding kinase 1 (TBK1) signaling pathway was observed in aged macrophages post‐IR and mitochondria DNA (mtDNA) stimulation. STING suppression blocked over‐activation of NLRP3 signaling and excessive secretion of proinflammatory cytokines/chemokines in the mtDNA‐stimulated BMDMs from aged mice. More importantly, STING knockdown in macrophages abrogated the detrimental role of aging in aggravating liver IR injury and intrahepatic inflammation. Finally, peripheral blood from the recipients undergoing liver transplantation was collected and analyzed. The results showed that the elderly recipients had much higher levels of TNF‐α, IL‐6, IL‐1β, and IL‐18 post‐transplantation, indicating increased NLRP3 activation in lR‐stressed livers of elderly recipients. In summary, our study demonstrated that the STING‐NLRP3 axis was critical for the proinflammatory response of aged macrophages and would be a novel therapeutic target to reduce IR injury in elderly patients. John Wiley and Sons Inc. 2020-07-14 2020-08 /pmc/articles/PMC7431827/ /pubmed/32666684 http://dx.doi.org/10.1111/acel.13186 Text en © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Zhong, Weizhe
Rao, Zhuqing
Rao, Jianhua
Han, Guoyong
Wang, Ping
Jiang, Tao
Pan, Xiongxiong
Zhou, Shun
Zhou, Haoming
Wang, Xuehao
Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages
title Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages
title_full Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages
title_fullStr Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages
title_full_unstemmed Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages
title_short Aging aggravated liver ischemia and reperfusion injury by promoting STING‐mediated NLRP3 activation in macrophages
title_sort aging aggravated liver ischemia and reperfusion injury by promoting sting‐mediated nlrp3 activation in macrophages
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431827/
https://www.ncbi.nlm.nih.gov/pubmed/32666684
http://dx.doi.org/10.1111/acel.13186
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