Figure 2.

Metabolic adaptations in activated macrophages. (A) Inflammatory macrophages are characterized by NO∙ -mediated inhibition of glucose flux in the Tricarboxylic Acid (TCA) cycle. NO∙ inhibits pyruvate dehydrogenase (PDH), aconitase 2 (ACO2), and SDH presumably through cysteine nitrosylation. This results in citrate accumulation and its conversion to itaconate which also blocks SDH. Citrate conversion to acetyl coA by ATP citrate lyase in the cytosol leads to histone acetylation and activation of inflammatory gene loci. SDH inhibition results in succinate accumulation, which inhibits PHDs, stabilizing HIF-1α and enhancing its transcriptional induction of glycolytic and inflammatory genes (e.g. pro-IL-1b). Succinylation of PKM2 leads to its inhibition and translocation to the nucleus where it promotes HIF-1α activity. RET mediated by succinate accumulation leads to ROS production. (B) Metabolic adaptations in M2 macrophages are represented in green. Macrophage tolerance in response to prolonged LPS exposure are in yellow.