IGF-2 Preprograms Maturing Macrophages to Acquire Oxidative Phosphorylation-Dependent Anti-inflammatory Properties

Recent investigations revealed that macrophages could be trained with an altered responsiveness, raising the possibility of combating autoimmune diseases by imparting anti-inflammatory capabilities to these cells. While investigating the effect of mesenchymal stem cells on experimental autoimmune encephalomyelitis (EAE), we found a critical role of insulin-like growth factor 2 (IGF-2) in training macrophages to become anti-inflammatory during their maturation. IGF-2 exerts its effects by preprogramming maturing macrophages to commit oxidative phosphorylation (OXPHOS). IGF-2-preprogrammed macrophages maintained the mitochondrial complex V activities even upon pro-inflammation stimulation, thus enabling an elevated programmed death-ligand 1 (PD-L1) expression. PD-L1 neutralization abolished the beneficial effect of IGF-2 on EAE. Furthermore, adoptive transfer of IGF-2-preprogrammed macrophages to EAE mice increased Tregs and alleviated the diseases. Our results demonstrate that shaping macrophage responsiveness by IGF-2 is effective in managing inflammatory diseases, and the OXPHOS commitment can be preset to determine the anti-inflammatory fate of macrophages. Du and Lin et al. show that insulin-like growth factor 2 (IGF-2) modulates the innate immune memory of macrophages during their maturation and enables macrophages to have persistent oxidative phosphorylation (OXPHOS). Such metabolic commitment allows macrophages to highly express PD-L1 even upon pro-inflammation stimulation and determines their anti-inflammatory phenotype.