Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages
Debabrata Chowdhury,
Hani Alrefai,
Julio A. Landero Figueroa,
Kathleen Candor,
Aleksey Porollo,
Roger Fecher,
Senad Divanovic,
George S. Deepe, Jr.,
Kavitha Subramanian Vignesh
Affiliations
Debabrata Chowdhury
Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
Hani Alrefai
Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
Julio A. Landero Figueroa
University of Cincinnati/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USA
Kathleen Candor
University of Cincinnati/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USA
Aleksey Porollo
Center for Autoimmune Genomics and Etiology and Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Roger Fecher
Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY 10467, USA
Senad Divanovic
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
George S. Deepe, Jr.
Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
Kavitha Subramanian Vignesh
Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Corresponding author
Summary: 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. Keywords: metallothionein 3, macrophage, polarization, metabolism, IL-4, HIF
