Pentose Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide Production Controlling Trypanosoma cruzi in Macrophages

Frontiers in Immunology

Bartosz Szczesny¹  Xianxiu Wan²  Nagireddy Putluri³  Sue-jie Koo⁴  Nisha Jain Garg⁵ 

[1] Department of Anesthesiology, University of Texas Medical Branch (UTMB), Galveston, TX, United States;Department of Microbiology and Immunology, University of Texas Medical Branch (UTMB), Galveston, TX, United States;Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, United States;Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, TX, United States;Institute for Human Infections and Immunity, University of Texas Medical Branch (UTMB), Galveston, TX, United States;

关键词: metabolism;    macrophages;    reactive oxygen species;    peroxisome proliferator-activated receptors;    NADPH;    Trypanosoma cruzi;   

DOI  :  10.3389/fimmu.2018.00202

来源: DOAJ

【 摘 要 】

Metabolism provides substrates for reactive oxygen species (ROS) and nitric oxide (NO) generation, which are a part of the macrophage (Mφ) anti-microbial response. Mφs 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 Mφs 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.

【 授权许可】

Unknown