Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation.巨噬细胞向不同功能状态的激活与极化过程，关键依赖于代谢转变的支持。目前学界对于极化信号如何协调代谢与功能重编程，以及调控巨噬细胞激活的潜在意义仍知之甚少。本研究发现，白细胞介素4（IL-4）信号通路会利用Akt-mTORC1通路，调控乙酰辅酶A（Ac-CoA）合成中的关键酶Acly，进而提升组蛋白乙酰化水平并诱导M2型巨噬细胞相关基因的表达。仅有部分M2型巨噬细胞相关基因通过该方式被调控，其中涵盖了调控细胞增殖与趋化因子产生的相关基因。此外，代谢信号可作用于Akt-mTORC1轴，从而实现对M2激活的此类调控。我们提出，Akt-mTORC1信号通路可将代谢状态校准至M2激活过程中能量需求较高的环节，这或许为代谢过程支持巨噬细胞激活的机制定义了全新的功能角色。