Figure 4.

Neutrophil metabolic pathways and the effect of their dysregulation in SLE and RA. (A) In physiological conditions, glycolysis is the main energy producing pathway utilized by neutrophils; intermediate metabolites G6P and F6P are starter molecules for the pentose phosphate pathway (PPP), important in redox control, NOX2-dependent NETosis and ROS production. The oxidative stage of PPP produces NADPH which is used in the glutathione metabolism to reduce glutathione providing further redox capacity. Other energy producing pathways have been described, previously thought to be non-functional, such as the TCA cycle which connects glutaminolysis pathway and further regulates NOX2 complex by generating the reducing equivalents of NADPH. (B) In SLE and RA dysregulation of these pathways is responsible for the conditions observed at the cellular level. In SLE (red arrows), a lower expression of glucose transporters is met with lower levels of intracellular glucose, diminishing the energy output by glycolysis and compromising cellular viability. Furthermore, a decrease of G6P intermediates correlates with lower levels of NOX2-dependent ROS and decreased redox capacity. NOX2-independent ROS production in mitochondria is amplified in SLE neutrophils with increasing release of NETs containing mitochondrial DNA. In RA (green arrows), the inflammatory environment and hypoxic conditions increase the expression of HIF1-α which upregulates key glycolytic enzymes increasing energy production and viability. HIF1-α also is an upstream regulator of NF-κB which increases pro-inflammatory cytokine production therefore maintaining the inflammatory environment.