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

TLDR

Macrophage activation and polarization rely on metabolic shifts, yet how polarizing signals coordinate metabolic and functional reprogramming to control activation remains poorly understood. The study proposes that Akt‑mTORC1 signaling calibrates the metabolic state to support energetically demanding aspects of M2 activation, revealing a new metabolic role in macrophage activation. IL‑4 activates the Akt‑mTORC1 pathway to regulate Acly, increasing Ac‑CoA synthesis, histone acetylation, and M2 gene induction. This pathway selectively controls a subset of M2 genes involved in proliferation and chemokine production, and metabolic signals modulate Akt‑mTORC1 to regulate M2 activation.

Abstract

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.