CD40 signal rewires fatty acid and glutamine metabolism for stimulating macrophage anti-tumorigenic functions

Exposure of lipopolysaccharide triggers macrophage pro-inflammatory polarization accompanied by metabolic reprogramming, characterized by elevated aerobic glycolysis and a broken tricarboxylic acid cycle. However, in contrast to lipopolysaccharide, CD40 signal is able to drive pro-inflammatory and anti-tumorigenic polarization by some yet undefined metabolic programming. Here we show that CD40 activation triggers fatty acid oxidation (FAO) and glutamine metabolism to promote ATP citrate lyase-dependent epigenetic reprogramming of pro-inflammatory genes and anti-tumorigenic phenotypes in macrophages. Mechanistically, glutamine usage reinforces FAO-induced pro-inflammatory and anti-tumorigenic activation by fine-tuning the NAD(+)/NADH ratio via glutamine-to-lactate conversion. Genetic ablation of important metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes agonistic anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages. Together these data show that metabolic reprogramming, which includes FAO and glutamine metabolism, controls the activation of pro-inflammatory and anti-tumorigenic polarization, and highlight a therapeutic potential of metabolic preconditioning of tumor-associated macrophages before agonistic anti-CD40 treatments. Unlike metabolic reprogramming that is characteristic of macrophage inflammatory polarization responses to lipopolysaccharide and TLR4 stimulation, the metabolism underlying inflammatory responses to CD40 signaling is not well characterized. Here the authors show CD40 signaling drives fatty acid oxidation and glutamine metabolism resulting in regulation of the NAD(+)/NADH ratio, which in turn promotes antitumor and pro-inflammatory macrophage functions.

Automated summary

Exposure to lipopolysaccharide leads to pro-inflammatory macrophage polarization and metabolic reprogramming, while CD40 signal drives both pro-inflammatory and anti-tumorigenic polarization through fatty acid oxidation and glutamine metabolism. Glutamine usage enhances the pro-inflammatory and anti-tumorigenic activation by regulating the NAD(+)/NADH ratio. Inhibition of metabolic enzymes involved in CD40-mediated metabolic reprogramming abolishes anti-CD40-induced antitumor responses and reeducation of tumor-associated macrophages.