Wang Xuefeng, Lin Liangyu, Lan Bin, Wang Yu, Du Liming, Chen Xiaodong, Li Qing, Liu Keli, Hu Mingyuan, Xue Yueqing, Roberts Arthur I, Shao Changshun, Melino Gerry, Shi Yufang, Wang Ying
CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
The First Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, 199 Renai Road, Suzhou, Jiangsu 215123, China.
Sci Adv. 2020 Nov 25;6(48). doi: 10.1126/sciadv.abb7389. Print 2020 Nov.
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.
胰岛素样生长因子2（IGF2）可重塑巨噬细胞的代谢特征；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中发挥双重且相反的作用，这依赖于低剂量IGF2（L-IGF2）对IGF2受体（IGF2R）的显性激活以及高剂量IGF2对IGF1R的激活。IGF2R激活导致质子重新通道化至线粒体内膜间隙，并实现持续的氧化磷酸化。从机制上讲，L-IGF2诱导IGF2R的核转位，通过激活GSK3α/β促进Dnmt3a介导的DNA甲基化，随后损害液泡型H-ATP酶（v-ATPase）的表达。v-ATPase的这种隔离组装抑制了质子向溶酶体的通道化，并导致它们重新通道化至线粒体。一种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方面以前未被识别的作用。
