IL-10/ACOD1 axis regulates catabolism of phagocytosed lipids in trained macrophages

Macrophages clear excess host and microbial debris to restore homeostasis in inflamed tissues, yet the regulation and molecular fate of phagocytosed lipids during innate immune training remains largely unexplored. Leveraging stable isotope tracing of ¹³ C-labeled bacteria, we establish an experimental framework to track microbe-to-host lipid transfer and define the fates of microbial lipids in macrophages in vitro and in vivo . While naïve macrophages scavenge phagocytosed bacterial fatty acids into the host lipidome, TLR4-trained macrophages direct flux to mitochondria for β-oxidation or lipid droplets in the context of mitochondrial dysfunction. While TLR4 signaling increases ACOD1 expression to produce itaconate that throttles TCA flux, trained macrophages produce IL-10 that reduces ACOD1 to sustain bacterial lipid disposal and promote resolution. These findings reveal an IL-10/ACOD1 regulatory axis in trained macrophages that reprograms lipid metabolism to optimally reestablish tissue homeostasis post-inflammation.