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A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke
Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative ph...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127063/ https://www.ncbi.nlm.nih.gov/pubmed/37098609 http://dx.doi.org/10.1186/s12974-023-02779-w |
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author | Ma, Wen-yu Wu, Qing-lin Wang, Sha-sha Wang, Hong-yun Ye, Jun-rui Sun, Hong-shuo Feng, Zhong-ping He, Wen-bin Chu, Shi-feng Zhang, Zhao Chen, Nai-hong |
author_facet | Ma, Wen-yu Wu, Qing-lin Wang, Sha-sha Wang, Hong-yun Ye, Jun-rui Sun, Hong-shuo Feng, Zhong-ping He, Wen-bin Chu, Shi-feng Zhang, Zhao Chen, Nai-hong |
author_sort | Ma, Wen-yu |
collection | PubMed |
description | Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR)–hypoxia inducible factor 1α (HIF-1α) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02779-w. |
format | Online Article Text |
id | pubmed-10127063 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-101270632023-04-26 A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke Ma, Wen-yu Wu, Qing-lin Wang, Sha-sha Wang, Hong-yun Ye, Jun-rui Sun, Hong-shuo Feng, Zhong-ping He, Wen-bin Chu, Shi-feng Zhang, Zhao Chen, Nai-hong J Neuroinflammation Research Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR)–hypoxia inducible factor 1α (HIF-1α) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02779-w. BioMed Central 2023-04-25 /pmc/articles/PMC10127063/ /pubmed/37098609 http://dx.doi.org/10.1186/s12974-023-02779-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Ma, Wen-yu Wu, Qing-lin Wang, Sha-sha Wang, Hong-yun Ye, Jun-rui Sun, Hong-shuo Feng, Zhong-ping He, Wen-bin Chu, Shi-feng Zhang, Zhao Chen, Nai-hong A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke |
title | A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke |
title_full | A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke |
title_fullStr | A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke |
title_full_unstemmed | A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke |
title_short | A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke |
title_sort | breakdown of metabolic reprogramming in microglia induced by cklf1 exacerbates immune tolerance in ischemic stroke |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127063/ https://www.ncbi.nlm.nih.gov/pubmed/37098609 http://dx.doi.org/10.1186/s12974-023-02779-w |
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