Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Ministry of Education, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University; Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin, 300070, China.
Institute for Genome Engineered Animal Models of Human Diseases, National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, 116044, Liaoning, China.
Cell Mol Immunol. 2022 Nov;19(11):1263-1278. doi: 10.1038/s41423-022-00925-7. Epub 2022 Sep 30.
Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK-STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.
丝氨酸代谢据称参与免疫细胞功能，但丝氨酸代谢如何调节巨噬细胞极化仍知之甚少。本文中，我们发现无论是通过抑制丝氨酸生物合成途径中的关键酶磷酸甘油酸脱氢酶的活性，还是通过外源性丝氨酸和甘氨酸限制，均能显著增强干扰素-γ激活的巨噬细胞（M(IFN-γ)）的极化，同时抑制白细胞介素-4 激活的巨噬细胞（M(IL-4)）的极化，无论是在体外还是体内。从机制上讲，丝氨酸代谢缺陷通过降低 S-腺苷甲硫氨酸依赖的组蛋白 H3 赖氨酸 27 三甲基化的启动子丰度，增加 IGF1 的表达。IGF1 随后激活 p38 依赖性 JAK-STAT1 轴，促进 M(IFN-γ)极化，并抑制 STAT6 介导的 M(IL-4)激活。本研究揭示了丝氨酸代谢协调巨噬细胞极化的新机制，并提示操纵丝氨酸代谢可能是治疗巨噬细胞介导的免疫疾病的一种策略。
