Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Immunobiology, Yale University, New Haven, CT; and.
J Immunol. 2021 Aug 1;207(3):913-922. doi: 10.4049/jimmunol.2100230. Epub 2021 Jul 21.
Metabolic programming is integrally linked to immune cell function. Nowhere is this clearer than in the differentiation of macrophages. Proinflammatory M1 macrophages primarily use glycolysis as a rapid energy source but also to generate antimicrobial compounds, whereas alternatively activated M2 macrophages primarily rely on oxidative phosphorylation for the longevity required for proper wound healing. mTOR signaling has been demonstrated to be a key regulator of immune cell metabolism and function. mTORC2 signaling is required for the generation of M2 macrophages, whereas the role of mTORC1 signaling, a key regulator of glycolysis, has been controversial. By using genetic deletion of mTORC1 signaling in C57BL/6 mouse macrophages, we observed enhanced M1 macrophage function in vitro and in vivo. Surprisingly, this enhancement occurred despite a significant defect in M1 macrophage glycolytic metabolism. Mechanistically, enhanced M1 function occurred because of inhibition of the class III histone deacetylases the sirtuins, resulting in enhanced histone acetylation. Our findings provide a counterpoint to the paradigm that enhanced immune cell function must occur in the presence of increased cellular metabolism and identifies a potential, pharmacologic target for the regulation of inflammatory responses.
代谢编程与免疫细胞功能密切相关。在巨噬细胞的分化中，这一点最为明显。促炎 M1 巨噬细胞主要利用糖酵解作为快速能量来源，同时也产生抗菌化合物，而另一种激活的 M2 巨噬细胞主要依赖氧化磷酸化来维持适当的伤口愈合所需的寿命。mTOR 信号已被证明是免疫细胞代谢和功能的关键调节剂。mTORC2 信号对于 M2 巨噬细胞的产生是必需的，而 mTORC1 信号（糖酵解的关键调节剂）的作用一直存在争议。通过在 C57BL/6 小鼠巨噬细胞中基因敲除 mTORC1 信号，我们观察到体外和体内 M1 巨噬细胞功能增强。令人惊讶的是，尽管 M1 巨噬细胞糖酵解代谢存在明显缺陷，但仍观察到这种增强。从机制上讲，M1 功能的增强是由于抑制了 III 类组蛋白去乙酰化酶——沉默调节蛋白，从而导致组蛋白乙酰化增强。我们的发现为增强免疫细胞功能必须在细胞代谢增加的情况下发生的范例提供了一个反例，并确定了调节炎症反应的一个潜在的、药理学靶点。
