RNA-seq of M0 vs M(IL-4) macrophages from WT and MT3 KO mice

Alternatively activated (M2) macrophages promote wound healing but weaken antimicrobial defenses. The mechanisms that enforce macrophages divergence and dictate the phenotypic and metabolic characteristics of M2 macrophages remain elusive. We show that alternative activation with interleukin (IL)-4 induces expression of metallothionein 3 (MT3) that regulates macrophage polarization and function. MT3 was requisite for metabolic reprograming in IL-4 treated macrophages or M2(IL-4) macrophages to promote mitochondrial respiration and suppress glycolysis. MT3 fostered an M2(IL-4) phenotype, suppressed hypoxia inducible factor (HIF)1-alpha activation and thwarted the emergence of a proinflammatory M1 program in macrophages. In vivo, MT3 deficiency augmented macrophage plasticity, resulting in enhanced interferon (IFN)gamma responsiveness and a dampened M2(IL-4) phenotype. Thus, MT3 programs the phenotype and metabolic fate of M2(IL-4) macrophages.