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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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