Figure 2.
Inflammatory and host defense effector mechanisms driven by citrate, succinate, and glycolysis. The activation of macrophages with LPS leads to a broken Krebs cycle. This leads to inflammatory mediators (in red), where succinate accumulates and activates HIF1α, which promotes IL-1β transcription. LPS also promotes glycolysis in which the enzyme HK1 also activates the NLRP3 inflammasome to promote pro–IL-1β processing. Citrate accumulation leads to the generation of prostaglandins, NO, and ROS. In host defense, citrate generates itaconate, which has a direct antibacterial effect (in green) inhibiting the glyoxylate shunt in bacteria (demonstrated for Salmonella and Mycobacteria), which decreases their viability. The orphan nuclear receptor ERRα is a well-known regulator of energy metabolism and mitochondrial biogenesis and has been shown to directly induce A20, a potent inhibitor of TLR4 signaling.