Metabolic traits of macrophages can be rewired by insulin-like growth factor 2 (IGF2); however, how IGF2 modulates macrophage cellular dynamics and functionality remains unclear. We demonstrate that IGF2 exhibits dual and opposing roles in controlling inflammatory phenotypes in macrophages by regulating glucose metabolism, relying on the dominant activation of the IGF2 receptor (IGF2R) by low-dose IGF2 (L-IGF2) and IGF1R by high-dose IGF2. IGF2R activation leads to proton rechanneling to the mitochondrial intermembrane space and enables sustained oxidative phosphorylation. Mechanistically, L-IGF2 induces nucleus translocation of IGF2R that promotes Dnmt3a-mediated DNA methylation by activating GSK3α/β and subsequently impairs expression of vacuolar-type H⁺-ATPase (v-ATPase). This sequestrated assembly of v-ATPase inhibits the channeling of protons to lysosomes and leads to their rechanneling to mitochondria. An IGF2R-specific IGF2 mutant induces only the anti-inflammatory response and inhibits colitis progression. Together, our findings highlight a previously unidentified role of IGF2R activation in dictating anti-inflammatory macrophages.

巨噬细胞的代谢特征可以通过胰岛素样生长因子 2 (IGF2) 重新连接；然而，IGF2 如何调节巨噬细胞的细胞动力学和功能仍不清楚。我们证明 IGF2 通过调节葡萄糖代谢在控制巨噬细胞炎症表型方面表现出双重和相反的作用，这依赖于低剂量 IGF2 (L-IGF2) 对 IGF2 受体 (IGF2R) 的显性激活和高剂量 IGF2 对 IGF1R 的显性激活。IGF2R 激活导致质子重新引导到线粒体膜间隙并实现持续的氧化磷酸化。机制上，L-IGF2 诱导 IGF2R 的核易位，通过激活 GSK3α/β 促进 Dnmt3a 介导的 DNA 甲基化，随后损害液泡型 H ^+的表达-ATP酶（v-ATP酶）。v-ATP酶的这种隔离组装抑制了质子向溶酶体的通道，并导致它们重新引导至线粒体。IGF2R 特异性 IGF2 突变体仅诱导抗炎反应并抑制结肠炎进展。总之，我们的研究结果突出了 IGF2R 激活在决定抗炎巨噬细胞中的先前未知作用。