mTORC2-IRF4 mediated metabolic reprograming is essential for macrophage alternative activation

Abstract

Changes in metabolism can be initiated in response to signals received from other cells. An example of this is provided by macrophages that have been stimulated by IL-4 to become alternatively/M2 activated. In these cells, fatty acid oxidation is increased and this is critical for M2 activation. Compared to resting macrophages, M2 macrophages also exhibit changes in glucose metabolism that we have found are essential for activation. In other cell types, mTORC2 has been linked to enhanced glycolysis. We have found that mTORC2 operates in parallel with the IL-4Rα/Stat6 pathway to facilitate increased glycolysis during M2 activation. Our data strongly implicate PI3K and AKT signaling initiated by M-CSF as components in this pathway, and indicate that downstream induction of IRF4 expression plays a role in metabolic reprograming to support M2 activation. We show that loss of mTORC2 in macrophages suppresses tumor growth and decreases immunity to a parasitic nematode.