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Glycolysis and the Pentose Phosphate Pathway Promote LPS-Induced NOX2 Oxidase- and IFN-β-Dependent Inflammation in Macrophages

Authors :
Jonathan R. Erlich
Eunice E. To
Raymond Luong
Felicia Liong
Stella Liong
Osezua Oseghale
Mark A. Miles
Steven Bozinovski
Robert D. Brooks
Ross Vlahos
Stanley Chan
John J. O’Leary
Doug A. Brooks
Stavros Selemidis
Source :
Antioxidants, Vol 11, Iss 8, p 1488 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

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.

Details

Language :
English
ISSN :
20763921
Volume :
11
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Antioxidants
Publication Type :
Academic Journal
Accession number :
edsdoj.83b0f2bd21c8471894b47e8cff871b29
Document Type :
article
Full Text :
https://doi.org/10.3390/antiox11081488