Pentose phosphate shunt modulates reactive oxygen species and nitric oxide production controlling Trypanosoma cruzi in Macrophages

Sue jie Koo, Bartosz Szczesny, Xianxiu Wan, Nagireddy Putluri, Nisha Jain Garg

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Metabolism provides substrates for reactive oxygen species (ROS) and nitric oxide (NO) generation, which are a part of the macrophage (MΦ) anti-microbial response. Mfs infected with Trypanosoma cruzi (Tc) produce insufficient levels of oxidative species and lower levels of glycolysis compared to classical MΦs. How MΦs fail to elicit a potent ROS/NO response during infection and its link to glycolysis is unknown. Herein, we evaluated for ROS, NO, and cytokine production in the presence of metabolic modulators of glycolysis and the Krebs cycle. Metabolic status was analyzed by Seahorse Flux Analyzer and mass spectrometry and validated by RNAi. Tc infection of RAW264.7 or bone marrow-derived Mfs elicited a substantial increase in peroxisome proliferator-activated receptor (PPAR)-α expression and pro-inflammatory cytokine release, and moderate levels of ROS/NO by 18 h. Interferon (IFN)-γ addition enhanced the Tc-induced ROS/NO release and shut down mitochondrial respiration to the levels noted in classical MΦs. Inhibition of PPAR-α attenuated the ROS/NO response and was insufficient for complete metabolic shift. Deprivation of glucose and inhibition of pyruvate transport showed that Krebs cycle and glycolysis support ROS/NO generation in Tc + IFN-γ stimulated MΦs. Metabolic profiling and RNAi studies showed that glycolysis-pentose phosphate pathway (PPP) at 6-phosphogluconate dehydrogenase was essential for ROS/NO response and control of parasite replication in MΦ. We conclude that IFN-γ, but not inhibition of PPAR-α, supports metabolic upregulation of glycolytic-PPP for eliciting potent ROS/NO response in Tc-infected MΦs. Chemical analogs enhancing the glucose-PPP will be beneficial in controlling Tc replication and dissemination by MΦs.

Original languageEnglish (US)
Article number202
JournalFrontiers in immunology
Volume9
Issue numberFEB
DOIs
StatePublished - Feb 16 2018

Keywords

  • Macrophages
  • Metabolism
  • NADPH
  • Pentose phosphate pathway
  • Peroxisome proliferator-activated receptors
  • Reactive oxygen species
  • Trypanosoma cruzi

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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