Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages

Alternatively activated (M2) macrophages promote wound healing but weaken antimicrobial defenses. The mechanisms that enforce macrophage 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-stimulated macrophages or M(IL-4) macrophages to promote mitochondrial respiration and suppress glycolysis. MT3 fostered an M(IL-4) phenotype, suppressed hypoxia inducible factor (HIF)1α activation, and thwarted the emergence of a proinflammatory M1 program in macrophages. MT3 deficiency augmented macrophage plasticity, resulting in enhanced interferon γ (IFNγ) responsiveness and a dampened M(IL-4) phenotype. Thus, MT3 programs the phenotype and metabolic fate of M(IL-4) macrophages. Metabolic reprograming in interleukin (IL)-4-stimulated macrophages (M(IL-4) macrophages) have a distinct polarization and metabolic phenotype. Chowdhury et al. show that metallothionein 3 (MT3) is required for M(IL-4) polarization and oxidative metabolism. MT3 suppresses glycolysis and the emergence of a proinflammatory M1 program. MT3 is a gatekeeper that subverts interferon (IFNγ) responses and intracellular defenses in M(IL-4) macrophages.