Figure 3.

Metabolic phenotype of classically LPS-activated macrophage. LPS activated macrophages are defined by a highly glycolytic phenotype with a disrupted tricarboxylic acid (TCA) cycle and attenuated cellular respiration. Recent studies employing carbon flux analysis identified two breaks in the TCA cycle, one at isocitrate dehydrogenase (IDH) and the other at succinate dehydrogenase (SDH). This phenomenon results in the accumulation of both citrate and succinate, key metabolic intermediates capable of functioning as inflammatory signaling mediators. While citrate functions as a precursor to itaconate, prostaglandins and ^•NO, succinate is capable of protein post-translational modification and stabilizing HIF-1α. Furthermore, accumulation of both succinate and reactive oxygen species (ROS) stabilize HIF-1α, thereby potentiating glucose utilization and downstream inflammatory programming. It has been posited that succinate accumulation in LPS-activated macrophages is the result of itaconate production and subsequent inhibition of SDH) Finally, two anaplerotic pathways are utilized by activated macrophage as a fuel source: the glutamine shunt and the arginosuccinate shunt. Together, these changes manifest in altered cellular metabolism to meet the bioenergetic demands of the cell.