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Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages
Macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis when exposed to gram-negative bacterial lipopolysaccharide (LPS), which modulates antibacterial host defence mechanisms. Here, we show that LPS treatment of macrophages increased the classical oxidative burst respons...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405479/ https://www.ncbi.nlm.nih.gov/pubmed/36009206 http://dx.doi.org/10.3390/antiox11081488 |
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author | Erlich, Jonathan R. To, Eunice E. Luong, Raymond Liong, Felicia Liong, Stella Oseghale, Osezua Miles, Mark A. Bozinovski, Steven Brooks, Robert D. Vlahos, Ross Chan, Stanley O’Leary, John J. Brooks, Doug A. Selemidis, Stavros |
author_facet | Erlich, Jonathan R. To, Eunice E. Luong, Raymond Liong, Felicia Liong, Stella Oseghale, Osezua Miles, Mark A. Bozinovski, Steven Brooks, Robert D. Vlahos, Ross Chan, Stanley O’Leary, John J. Brooks, Doug A. Selemidis, Stavros |
author_sort | Erlich, Jonathan R. |
collection | PubMed |
description | Macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis when exposed to gram-negative bacterial lipopolysaccharide (LPS), which modulates antibacterial host defence mechanisms. Here, we show that LPS treatment of macrophages increased the classical oxidative burst response via the NADPH oxidase (NOX) 2 enzyme, which was blocked by 2-deoxyglucose (2-DG) inhibition of glycolysis. The inhibition of the pentose phosphate pathway with 6-aminonicotinamide (6-AN) also suppressed the LPS-induced increase in NOX2 activity and was associated with a significant reduction in the mRNA expression of NOX2 and its organizer protein p47phox. Notably, the LPS-dependent enhancement in NOX2 oxidase activity was independent of both succinate and mitochondrial reactive oxygen species (ROS) production. LPS also increased type I IFN-β expression, which was suppressed by 2-DG and 6-AN and, therefore, is dependent on glycolysis and the pentose phosphate pathway. The type I IFN-β response to LPS was also inhibited by apocynin pre-treatment, suggesting that NOX2-derived ROS promotes the TLR4-induced response to LPS. Moreover, recombinant IFN-β increased NOX2 oxidase-dependent ROS production, as well as NOX2 and p47phox expression. Our findings identify a previously undescribed molecular mechanism where both glycolysis and the pentose phosphate pathway are required to promote LPS-induced inflammation in macrophages. |
format | Online Article Text |
id | pubmed-9405479 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94054792022-08-26 Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages Erlich, Jonathan R. To, Eunice E. Luong, Raymond Liong, Felicia Liong, Stella Oseghale, Osezua Miles, Mark A. Bozinovski, Steven Brooks, Robert D. Vlahos, Ross Chan, Stanley O’Leary, John J. Brooks, Doug A. Selemidis, Stavros Antioxidants (Basel) Article Macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis when exposed to gram-negative bacterial lipopolysaccharide (LPS), which modulates antibacterial host defence mechanisms. Here, we show that LPS treatment of macrophages increased the classical oxidative burst response via the NADPH oxidase (NOX) 2 enzyme, which was blocked by 2-deoxyglucose (2-DG) inhibition of glycolysis. The inhibition of the pentose phosphate pathway with 6-aminonicotinamide (6-AN) also suppressed the LPS-induced increase in NOX2 activity and was associated with a significant reduction in the mRNA expression of NOX2 and its organizer protein p47phox. Notably, the LPS-dependent enhancement in NOX2 oxidase activity was independent of both succinate and mitochondrial reactive oxygen species (ROS) production. LPS also increased type I IFN-β expression, which was suppressed by 2-DG and 6-AN and, therefore, is dependent on glycolysis and the pentose phosphate pathway. The type I IFN-β response to LPS was also inhibited by apocynin pre-treatment, suggesting that NOX2-derived ROS promotes the TLR4-induced response to LPS. Moreover, recombinant IFN-β increased NOX2 oxidase-dependent ROS production, as well as NOX2 and p47phox expression. Our findings identify a previously undescribed molecular mechanism where both glycolysis and the pentose phosphate pathway are required to promote LPS-induced inflammation in macrophages. MDPI 2022-07-29 /pmc/articles/PMC9405479/ /pubmed/36009206 http://dx.doi.org/10.3390/antiox11081488 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Erlich, Jonathan R. To, Eunice E. Luong, Raymond Liong, Felicia Liong, Stella Oseghale, Osezua Miles, Mark A. Bozinovski, Steven Brooks, Robert D. Vlahos, Ross Chan, Stanley O’Leary, John J. Brooks, Doug A. Selemidis, Stavros Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages |
title | Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages |
title_full | Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages |
title_fullStr | Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages |
title_full_unstemmed | Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages |
title_short | Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages |
title_sort | glycolysis and the pentose phosphate pathway promote lps-induced nox2 oxidase- and ifn-β-dependent inflammation in macrophages |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405479/ https://www.ncbi.nlm.nih.gov/pubmed/36009206 http://dx.doi.org/10.3390/antiox11081488 |
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