According to their function, macrophages can be classified as pro-inflammatory macrophages or M1 that are defined by the response to interferon-γ (IFN-γ) and the activation of Toll-like receptors (TLRs) and anti-inflammatory macrophages or M2 that are defined by responses to IL-4 and IL-13. Strategies for anti-inflammatory macrophage induction have attracted much attention to combat inflammatory diseases.

By testing the receptor(s) in mediating the role of IGF2 in treating inflammatory diseases, the researchers found that IGF2 in low-dose acts through IGF2R and alleviates colitis via promoting anti-inflammatory macrophages, while IGF2 in high dose works on IGF1R and aggravates colitis via enhancing pro-inflammatory macrophages.

More importantly, they found that IGF2R ligation with IGF2 can induce its nuclear translocation and promote the binding of GSK3α/β to chromatin, and maintain the hypermethylation state of V-ATPase-related genes. Such hypermethylation impaired the assembly of v-ATPase and lysosomal acidification during macrophage maturation, leading to the accumulation of protons in cytosolic and their distribution into mitochondrial membrane space in a chemical gradient manner.

Enhanced protons in mitochondrial membrane space promote oxidative phosphorylation (OXPHOS), and set macrophages in an anti-inflammatory properties. Specifically targeting IGF2R can persistently induce anti-inflammatory macrophages and significantly inhibit inflammatory diseases, like peritonitis and colitis.

This study highlighted a novel mechanism of IGF2 family in controlling the generation of anti-inflammatory macrophages and provided novel strategies for the treatment of inflammatory diseases.

This study was published online in Science Advances. The finding is the continuity of the study of Drs. SHI Yufang and WANG Ying’s group published in Cell Metabolism in 2019 which reported the role of IGF2 in set macrophages in an inclination for OXPHOS and dictating their anti-inflammatory function.