Cargando…

PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control

BACKGROUND: Dendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been chara...

Descripción completa

Detalles Bibliográficos
Autores principales: Wu, You, Chen, Longwang, Qiu, Zhimin, Zhang, Xijing, Zhao, Guangju, Lu, Zhongqiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945621/
https://www.ncbi.nlm.nih.gov/pubmed/36809929
http://dx.doi.org/10.1186/s10020-023-00618-5
_version_ 1784892176611672064
author Wu, You
Chen, Longwang
Qiu, Zhimin
Zhang, Xijing
Zhao, Guangju
Lu, Zhongqiu
author_facet Wu, You
Chen, Longwang
Qiu, Zhimin
Zhang, Xijing
Zhao, Guangju
Lu, Zhongqiu
author_sort Wu, You
collection PubMed
description BACKGROUND: Dendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been characterized as a guide for impaired mitochondria that can keep mitochondrial homeostasis. However, its role in the function of DCs during sepsis and the related mechanisms remain obscure. In our study, we elucidated the effect of PINK1 on DC function during sepsis and its underlying mechanism of action. METHODS: Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) treatment were used as in vivo and in vitro sepsis models, respectively. RESULTS: We found that changes in mitochondrial PINK1 expression of DCs paralleled changes in DC function during sepsis. The ratio of DCs expressing MHC-II, CD86, and CD80, the mRNAs level of dendritic cells expressing TNF-α and IL-12, and the level of DC-mediated T-cell proliferation were all decreased, both in vivo and in vitro during sepsis, when PINK1 was knocked out. This suggested that PINK1 knockout prevented the function of DCs during sepsis. Furthermore, PINK1 knockout inhibited Parkin RBR E3 ubiquitin protein (Parkin)-dependent mitophagy and enhanced dynamin-related protein 1 (Drp1)-related mitochondrial fission, and the negative effects of PINK1 knockout on DC function following LPS treatment were reversed by Parkin activation and Drp1 inhibitor. Knockout of PINK1 also increased apoptosis of DCs and the mortality of CLP mice. CONCLUSION: Our results indicated that PINK1 protected against DC dysfunction during sepsis through the regulation of mitochondrial quality control. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00618-5.
format Online
Article
Text
id pubmed-9945621
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-99456212023-02-23 PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control Wu, You Chen, Longwang Qiu, Zhimin Zhang, Xijing Zhao, Guangju Lu, Zhongqiu Mol Med Research Article BACKGROUND: Dendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been characterized as a guide for impaired mitochondria that can keep mitochondrial homeostasis. However, its role in the function of DCs during sepsis and the related mechanisms remain obscure. In our study, we elucidated the effect of PINK1 on DC function during sepsis and its underlying mechanism of action. METHODS: Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) treatment were used as in vivo and in vitro sepsis models, respectively. RESULTS: We found that changes in mitochondrial PINK1 expression of DCs paralleled changes in DC function during sepsis. The ratio of DCs expressing MHC-II, CD86, and CD80, the mRNAs level of dendritic cells expressing TNF-α and IL-12, and the level of DC-mediated T-cell proliferation were all decreased, both in vivo and in vitro during sepsis, when PINK1 was knocked out. This suggested that PINK1 knockout prevented the function of DCs during sepsis. Furthermore, PINK1 knockout inhibited Parkin RBR E3 ubiquitin protein (Parkin)-dependent mitophagy and enhanced dynamin-related protein 1 (Drp1)-related mitochondrial fission, and the negative effects of PINK1 knockout on DC function following LPS treatment were reversed by Parkin activation and Drp1 inhibitor. Knockout of PINK1 also increased apoptosis of DCs and the mortality of CLP mice. CONCLUSION: Our results indicated that PINK1 protected against DC dysfunction during sepsis through the regulation of mitochondrial quality control. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00618-5. BioMed Central 2023-02-21 /pmc/articles/PMC9945621/ /pubmed/36809929 http://dx.doi.org/10.1186/s10020-023-00618-5 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/) .
spellingShingle Research Article
Wu, You
Chen, Longwang
Qiu, Zhimin
Zhang, Xijing
Zhao, Guangju
Lu, Zhongqiu
PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control
title PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control
title_full PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control
title_fullStr PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control
title_full_unstemmed PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control
title_short PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control
title_sort pink1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9945621/
https://www.ncbi.nlm.nih.gov/pubmed/36809929
http://dx.doi.org/10.1186/s10020-023-00618-5
work_keys_str_mv AT wuyou pink1protectsagainstdendriticcelldysfunctionduringsepsisthroughtheregulationofmitochondrialqualitycontrol
AT chenlongwang pink1protectsagainstdendriticcelldysfunctionduringsepsisthroughtheregulationofmitochondrialqualitycontrol
AT qiuzhimin pink1protectsagainstdendriticcelldysfunctionduringsepsisthroughtheregulationofmitochondrialqualitycontrol
AT zhangxijing pink1protectsagainstdendriticcelldysfunctionduringsepsisthroughtheregulationofmitochondrialqualitycontrol
AT zhaoguangju pink1protectsagainstdendriticcelldysfunctionduringsepsisthroughtheregulationofmitochondrialqualitycontrol
AT luzhongqiu pink1protectsagainstdendriticcelldysfunctionduringsepsisthroughtheregulationofmitochondrialqualitycontrol