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FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion

BACKGROUND: Traumatic spinal cord injury (SCI)-induced neuroinflammation results in secondary neurological destruction and functional disorder. Previous findings showed that microglial pyroptosis plays a crucial role in neuroinflammation. Thus, it is necessary to conduct a comprehensive investigatio...

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Autores principales: Xia, Mingjie, Li, Xinyu, Ye, Suhui, Zhang, Qinyang, Zhao, Tianyu, Li, Rulin, Zhang, Yanan, Xian, Minghan, Li, Tianqi, Li, Haijun, Hong, Xin, Zheng, Shengnai, Qian, Zhanyang, Yang, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164466/
https://www.ncbi.nlm.nih.gov/pubmed/35659106
http://dx.doi.org/10.1186/s13578-022-00816-4
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author Xia, Mingjie
Li, Xinyu
Ye, Suhui
Zhang, Qinyang
Zhao, Tianyu
Li, Rulin
Zhang, Yanan
Xian, Minghan
Li, Tianqi
Li, Haijun
Hong, Xin
Zheng, Shengnai
Qian, Zhanyang
Yang, Lei
author_facet Xia, Mingjie
Li, Xinyu
Ye, Suhui
Zhang, Qinyang
Zhao, Tianyu
Li, Rulin
Zhang, Yanan
Xian, Minghan
Li, Tianqi
Li, Haijun
Hong, Xin
Zheng, Shengnai
Qian, Zhanyang
Yang, Lei
author_sort Xia, Mingjie
collection PubMed
description BACKGROUND: Traumatic spinal cord injury (SCI)-induced neuroinflammation results in secondary neurological destruction and functional disorder. Previous findings showed that microglial pyroptosis plays a crucial role in neuroinflammation. Thus, it is necessary to conduct a comprehensive investigation of the mechanisms associated with post-SCI microglial pyroptosis. The Fanconi Anemia Group C complementation group gene (FANCC) has been previously reported to have an anti-inflammation effect; however, whether it can regulate microglial pyroptosis remains unknown. Therefore, we probed the mechanism associated with FANCC-mediated microglial pyroptosis and neuroinflammation in vitro and in vivo in SCI mice. METHODS: Microglial pyroptosis was assessed by western blotting (WB) and immunofluorescence (IF), whereas microglial-induced neuroinflammation was evaluated by WB, Enzyme-linked immunosorbent assays and IF. Besides, flow cytometry, TdT-mediated dUTP Nick-End Labeling staining and WB were employed to examine the level of neuronal apoptosis. Morphological changes in neurons were assessed by hematoxylin–eosin and Luxol Fast Blue staining. Finally, locomotor function rehabilitation was analyzed using the Basso Mouse Scale and Louisville Swim Scale. RESULTS: Overexpression of FANCC suppressed microglial pyroptosis via inhibiting p38/NLRP3 expression, which in turn reduced neuronal apoptosis. By contrast, knockdown of FANCC increased the degree of neuronal apoptosis by aggravating microglial pyroptosis. Besides, increased glial scar formation, severe myelin sheath destruction and poor axon outgrowth were observed in the mice transfected with short hairpin RNA of FANCC post SCI, which caused reduced locomotor function recovery. CONCLUSIONS: Taken together, a previously unknown role of FANCC was identified in SCI, where its deficiency led to microglia pyroptosis, neuronal apoptosis and neurological damage. Mechanistically, FANCC mediated microglia pyroptosis and the inflammatory response via regulating the p38/NLRP3 pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-022-00816-4.
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spelling pubmed-91644662022-06-05 FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion Xia, Mingjie Li, Xinyu Ye, Suhui Zhang, Qinyang Zhao, Tianyu Li, Rulin Zhang, Yanan Xian, Minghan Li, Tianqi Li, Haijun Hong, Xin Zheng, Shengnai Qian, Zhanyang Yang, Lei Cell Biosci Research BACKGROUND: Traumatic spinal cord injury (SCI)-induced neuroinflammation results in secondary neurological destruction and functional disorder. Previous findings showed that microglial pyroptosis plays a crucial role in neuroinflammation. Thus, it is necessary to conduct a comprehensive investigation of the mechanisms associated with post-SCI microglial pyroptosis. The Fanconi Anemia Group C complementation group gene (FANCC) has been previously reported to have an anti-inflammation effect; however, whether it can regulate microglial pyroptosis remains unknown. Therefore, we probed the mechanism associated with FANCC-mediated microglial pyroptosis and neuroinflammation in vitro and in vivo in SCI mice. METHODS: Microglial pyroptosis was assessed by western blotting (WB) and immunofluorescence (IF), whereas microglial-induced neuroinflammation was evaluated by WB, Enzyme-linked immunosorbent assays and IF. Besides, flow cytometry, TdT-mediated dUTP Nick-End Labeling staining and WB were employed to examine the level of neuronal apoptosis. Morphological changes in neurons were assessed by hematoxylin–eosin and Luxol Fast Blue staining. Finally, locomotor function rehabilitation was analyzed using the Basso Mouse Scale and Louisville Swim Scale. RESULTS: Overexpression of FANCC suppressed microglial pyroptosis via inhibiting p38/NLRP3 expression, which in turn reduced neuronal apoptosis. By contrast, knockdown of FANCC increased the degree of neuronal apoptosis by aggravating microglial pyroptosis. Besides, increased glial scar formation, severe myelin sheath destruction and poor axon outgrowth were observed in the mice transfected with short hairpin RNA of FANCC post SCI, which caused reduced locomotor function recovery. CONCLUSIONS: Taken together, a previously unknown role of FANCC was identified in SCI, where its deficiency led to microglia pyroptosis, neuronal apoptosis and neurological damage. Mechanistically, FANCC mediated microglia pyroptosis and the inflammatory response via regulating the p38/NLRP3 pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-022-00816-4. BioMed Central 2022-06-03 /pmc/articles/PMC9164466/ /pubmed/35659106 http://dx.doi.org/10.1186/s13578-022-00816-4 Text en © The Author(s) 2022 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
Xia, Mingjie
Li, Xinyu
Ye, Suhui
Zhang, Qinyang
Zhao, Tianyu
Li, Rulin
Zhang, Yanan
Xian, Minghan
Li, Tianqi
Li, Haijun
Hong, Xin
Zheng, Shengnai
Qian, Zhanyang
Yang, Lei
FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion
title FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion
title_full FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion
title_fullStr FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion
title_full_unstemmed FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion
title_short FANCC deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion
title_sort fancc deficiency mediates microglial pyroptosis and secondary neuronal apoptosis in spinal cord contusion
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164466/
https://www.ncbi.nlm.nih.gov/pubmed/35659106
http://dx.doi.org/10.1186/s13578-022-00816-4
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