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Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages
Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found tha...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906364/ https://www.ncbi.nlm.nih.gov/pubmed/31827178 http://dx.doi.org/10.1038/s41598-019-55295-4 |
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author | Ahmed, Duale Roy, David Jaworski, Allison Edwards, Alexander Abizaid, Alfonso Kumar, Ashok Golshani, Ashkan Cassol, Edana |
author_facet | Ahmed, Duale Roy, David Jaworski, Allison Edwards, Alexander Abizaid, Alfonso Kumar, Ashok Golshani, Ashkan Cassol, Edana |
author_sort | Ahmed, Duale |
collection | PubMed |
description | Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with differential accumulation of mitochondrial and cytosolic ROS, which were required to support ligand specific inflammatory and antiviral cytokine production. We also found that the magnitude of TLR3, but not TLR4, responses were modulated by glucose availability. Under conditions of low glucose, TLR3 engagement was associated with increased ETC complex III expression, increased mitochondrial and cytosolic ROS and increased inflammatory and antiviral cytokine production. This amplification was selectively reversed by targeting superoxide production from the outer Q-binding site of the ETC complex III. These results suggest that ligand specific modulation of the ETC may act as a rheostat that fine tunes innate immune responses via mitochondrial ROS production. Modulation of these processes may represent a novel mechanism to modulate the nature as well as the magnitude of antiviral vs. inflammatory immune responses. |
format | Online Article Text |
id | pubmed-6906364 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69063642019-12-13 Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages Ahmed, Duale Roy, David Jaworski, Allison Edwards, Alexander Abizaid, Alfonso Kumar, Ashok Golshani, Ashkan Cassol, Edana Sci Rep Article Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with differential accumulation of mitochondrial and cytosolic ROS, which were required to support ligand specific inflammatory and antiviral cytokine production. We also found that the magnitude of TLR3, but not TLR4, responses were modulated by glucose availability. Under conditions of low glucose, TLR3 engagement was associated with increased ETC complex III expression, increased mitochondrial and cytosolic ROS and increased inflammatory and antiviral cytokine production. This amplification was selectively reversed by targeting superoxide production from the outer Q-binding site of the ETC complex III. These results suggest that ligand specific modulation of the ETC may act as a rheostat that fine tunes innate immune responses via mitochondrial ROS production. Modulation of these processes may represent a novel mechanism to modulate the nature as well as the magnitude of antiviral vs. inflammatory immune responses. Nature Publishing Group UK 2019-12-11 /pmc/articles/PMC6906364/ /pubmed/31827178 http://dx.doi.org/10.1038/s41598-019-55295-4 Text en © The Author(s) 2019 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Ahmed, Duale Roy, David Jaworski, Allison Edwards, Alexander Abizaid, Alfonso Kumar, Ashok Golshani, Ashkan Cassol, Edana Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages |
title | Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages |
title_full | Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages |
title_fullStr | Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages |
title_full_unstemmed | Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages |
title_short | Differential remodeling of the electron transport chain is required to support TLR3 and TLR4 signaling and cytokine production in macrophages |
title_sort | differential remodeling of the electron transport chain is required to support tlr3 and tlr4 signaling and cytokine production in macrophages |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906364/ https://www.ncbi.nlm.nih.gov/pubmed/31827178 http://dx.doi.org/10.1038/s41598-019-55295-4 |
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