Pro-inflammatory macrophage activation does not require inhibition of oxidative phosphorylation.

Pro-inflammatory macrophage activation is a hallmark example of how mitochondria serve as signaling organelles. Oxidative phosphorylation sharply decreases upon classical macrophage activation, as mitochondria are thought to shift from ATP production towards accumulating signals that amplify effector function. However, evidence is conflicting regarding whether this collapse in respiration is essential or dispensable. Here we systematically examine this question and show that reduced oxidative phosphorylation is not required for pro-inflammatory macrophage activation. Different pro-inflammatory stimuli elicit varying effects on bioenergetic parameters, and pharmacologic and genetic models of electron transport chain inhibition show no causative link between respiration and macrophage activation. Furthermore, the signaling metabolites succinate and itaconate can accumulate independently of characteristic breaks in the TCA cycle in mouse and human macrophages, and peritoneal macrophages can be activated in vivo without inhibition of oxidative phosphorylation. The results indicate there is plasticity in the metabolic phenotypes that can support pro-inflammatory macrophage activation.