Metabolism Fine-tunes Macrophage Activation

C ells continually monitor the availability of nutrients and alter their activities and metabolism accordingly. Immune cells are no exception (O’Neill and Pearce, 2015). Macrophages are important immune cells that perform many roles – they are, for example, involved in development and wound repair – but they need to be activated before they can carry out their functions. For years it was thought that there were two major subsets of activated macrophages: M1 macrophages that promote inflammation, and M2 macrophages that suppress the immune response. In reality, the distinction between the subsets is less clear, although it is thought that M1 and M2 macrophages have different metabolic profiles and phenotypes (O’Neill and Pearce, 2015). Nevertheless, it is poorly understood how metabolism contributes to the control of gene expression during the activation of immune cells, and how metabolism promotes the M2 phenotype in particular. Now, in eLife, Tiffany Horng and colleagues – including Anthony Covarrubias as the first author – report on a signaling pathway that rewires the macrophage’s metabolism for the M2 phenotype (Covarrubias et al., 2016). First, they analyzed the metabolism of mouse macrophages that had been stimulated with a signaling molecule called interleukin 4 (IL-4) and confirmed several of the metabolic characteristics that were already known about M2 macrophages (e.g. that they show increased breakdown of fatty acids and oxidative phosphorylation in the mitochondria). However, the data also showed a characteristic that had previously been associated with the M1 phenotype (up-regulation of glycolysis). Covarrubias et al. went on to confirm that IL-4 triggered the uptake of glucose in a manner that depended on the kinase Akt. This kinase is well known as a key regulator of glucose uptake and metabolism (Pavlova and Thompson, 2016), and Covarrubias et al show that inhibiting Akt was shown to blunt the activation of some, but not all, M2 genes in response to IL-4. These initial observations prompted Covarrubias et al. – who are based at Harvard, the University of Pennsylvania, Brigham and Women’s Hospital, the Chinese Academy of Sciences, Drexel University and the University of Wisconsin-Madison – to investigate how the pathway that acts through IL-4 and Akt regulates specific M2 genes. Previously Akt activation had been shown to promote the phosphorylation of an enzyme called ATP-citrate lyase (or Acly for short). This enzyme converts citrate into acetylCopyright Torres et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Related research article Covarrubias AJ,