Cargando…

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,...

Descripción completa

Detalles Bibliográficos
Autores principales: Lu, Peng, Zheng, Huayong, Meng, Hao, Liu, Chuan, Duan, Lianhong, Zhang, Jianzheng, Zhang, Zhicheng, Gao, Jie, Zhang, Yang, Sun, Tiansheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
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
_version_ 1785059712288423936
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
work_keys_str_mv AT lupeng mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT zhenghuayong mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT menghao mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT liuchuan mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT duanlianhong mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT zhangjianzheng mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT zhangzhicheng mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT gaojie mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT zhangyang mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis
AT suntiansheng mitochondrialdnainducesnucleuspulposuscellpyroptosisviathetlr9nfkbnlrp3axis