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Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis
BACKGROUND: Nucleus pulposus cell (NPC) death and progressive reduction play important roles in intervertebral disc degeneration (IVDD). As part of a damage-associated molecular pattern, mitochondrial DNA (mtDNA) can be recognized by TLR9 and triggers the expression of NF-κB and NLRP3 inflammasomes,...
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/PMC10273761/ https://www.ncbi.nlm.nih.gov/pubmed/37322517 http://dx.doi.org/10.1186/s12967-023-04266-5 |
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author | Lu, Peng Zheng, Huayong Meng, Hao Liu, Chuan Duan, Lianhong Zhang, Jianzheng Zhang, Zhicheng Gao, Jie Zhang, Yang Sun, Tiansheng |
author_facet | Lu, Peng Zheng, Huayong Meng, Hao Liu, Chuan Duan, Lianhong Zhang, Jianzheng Zhang, Zhicheng Gao, Jie Zhang, Yang Sun, Tiansheng |
author_sort | Lu, Peng |
collection | PubMed |
description | BACKGROUND: Nucleus pulposus cell (NPC) death and progressive reduction play important roles in intervertebral disc degeneration (IVDD). As part of a damage-associated molecular pattern, mitochondrial DNA (mtDNA) can be recognized by TLR9 and triggers the expression of NF-κB and NLRP3 inflammasomes, inducing pyroptosis and inflammatory response. However, whether mtDNA induces NPC pyroptosis via the TLR9-NF-κB-NLRP3 axis and promotes IVDD remains uncertain. METHODS: We constructed an in vitro NPC oxidative stress injury model to clarify the mechanism of mtDNA release, TLR9-NF-κB signaling pathway activation, and NPC injury. We further verified the mechanism of action underlying the inhibition of mtDNA release or TLR9 activation in NPC injury in vitro. We then constructed a rat punctured IVDD model to understand the mechanism inhibiting mtDNA release and TLR9 activation in IVDD. RESULTS: We used human NP specimen assays to show that the expression levels of TLR9, NF-κB, and NLRP3 inflammasomes correlated with the degree of IVDD. We demonstrated that mtDNA mediated TLR9-NF-κB-NLRP3 axis activation in oxidative stress-induced human NPC pyroptosis in vitro. Oxidative stress can damage the mitochondria of NPCs, causing the opening of the mitochondrial permeability transition pores (mPTP) and leading to the release of mtDNA into the cytosol. Furthermore, inhibition of mPTP opening or TLR9 activation blocked TLR9-NF-κB-NLRP3 axis activation and thereby mediated NPC pyroptosis and IVDD. CONCLUSION: mtDNA plays a key role in mediating NPC pyroptosis and IVDD via the TLR9-NF-κB-NLRP3 axis. Our findings provide new potential targets for IVDD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04266-5. |
format | Online Article Text |
id | pubmed-10273761 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-102737612023-06-17 Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis Lu, Peng Zheng, Huayong Meng, Hao Liu, Chuan Duan, Lianhong Zhang, Jianzheng Zhang, Zhicheng Gao, Jie Zhang, Yang Sun, Tiansheng J Transl Med Research BACKGROUND: Nucleus pulposus cell (NPC) death and progressive reduction play important roles in intervertebral disc degeneration (IVDD). As part of a damage-associated molecular pattern, mitochondrial DNA (mtDNA) can be recognized by TLR9 and triggers the expression of NF-κB and NLRP3 inflammasomes, inducing pyroptosis and inflammatory response. However, whether mtDNA induces NPC pyroptosis via the TLR9-NF-κB-NLRP3 axis and promotes IVDD remains uncertain. METHODS: We constructed an in vitro NPC oxidative stress injury model to clarify the mechanism of mtDNA release, TLR9-NF-κB signaling pathway activation, and NPC injury. We further verified the mechanism of action underlying the inhibition of mtDNA release or TLR9 activation in NPC injury in vitro. We then constructed a rat punctured IVDD model to understand the mechanism inhibiting mtDNA release and TLR9 activation in IVDD. RESULTS: We used human NP specimen assays to show that the expression levels of TLR9, NF-κB, and NLRP3 inflammasomes correlated with the degree of IVDD. We demonstrated that mtDNA mediated TLR9-NF-κB-NLRP3 axis activation in oxidative stress-induced human NPC pyroptosis in vitro. Oxidative stress can damage the mitochondria of NPCs, causing the opening of the mitochondrial permeability transition pores (mPTP) and leading to the release of mtDNA into the cytosol. Furthermore, inhibition of mPTP opening or TLR9 activation blocked TLR9-NF-κB-NLRP3 axis activation and thereby mediated NPC pyroptosis and IVDD. CONCLUSION: mtDNA plays a key role in mediating NPC pyroptosis and IVDD via the TLR9-NF-κB-NLRP3 axis. Our findings provide new potential targets for IVDD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04266-5. BioMed Central 2023-06-15 /pmc/articles/PMC10273761/ /pubmed/37322517 http://dx.doi.org/10.1186/s12967-023-04266-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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 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 Lu, Peng Zheng, Huayong Meng, Hao Liu, Chuan Duan, Lianhong Zhang, Jianzheng Zhang, Zhicheng Gao, Jie Zhang, Yang Sun, Tiansheng Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis |
title | Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis |
title_full | Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis |
title_fullStr | Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis |
title_full_unstemmed | Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis |
title_short | Mitochondrial DNA induces nucleus pulposus cell pyroptosis via the TLR9-NF-κB-NLRP3 axis |
title_sort | mitochondrial dna induces nucleus pulposus cell pyroptosis via the tlr9-nf-κb-nlrp3 axis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10273761/ https://www.ncbi.nlm.nih.gov/pubmed/37322517 http://dx.doi.org/10.1186/s12967-023-04266-5 |
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