4.7 Article

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

期刊

ANTIOXIDANTS
卷 11, 期 8, 页码 -

出版社

MDPI
DOI: 10.3390/antiox11081488

关键词

inflammation; macrophages; NADPH oxidase; NOX2; LPS; glycolysis; pentose phosphate pathway; reactive oxygen species

资金

  1. Australian Research Council (ARC) [FT120100876]
  2. National Health and Medical Research Council of Australia (NHMRC) [1122506, 1128276]
  3. Australian Government Research Training Program (RTP) Scholarship
  4. Australian Research Council [FT120100876] Funding Source: Australian Research Council

向作者/读者索取更多资源

The study reveals that macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis when exposed to gram-negative bacterial lipopolysaccharide (LPS). This switch modulates antibacterial host defence mechanisms by increasing the activity of NOX2 enzyme and promoting the expression of type I IFN-beta. Both glycolysis and the pentose phosphate pathway play important roles in promoting LPS-induced 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 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-beta 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-beta 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-beta 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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