MYC-mediated early glycolysis negatively regulates proinflammatory responses by controlling IRF4 in inflammatory macrophages
Seyeon Bae,
Peter Sang Uk Park,
Yeji Lee,
Se Hwan Mun,
Eugenia Giannopoulou,
Takayuki Fujii,
Kelvin P. Lee,
Sara Nunes Violante,
Justin R. Cross,
Kyung-Hyun Park-Min
Affiliations
Seyeon Bae
Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA
Peter Sang Uk Park
Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA
Yeji Lee
Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA
Se Hwan Mun
Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA
Eugenia Giannopoulou
Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA; Biological Sciences Department, New York City College of Technology, City University of New York, Brooklyn, NY, USA
Takayuki Fujii
Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA; Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Kelvin P. Lee
Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Sara Nunes Violante
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Justin R. Cross
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Kyung-Hyun Park-Min
Arthritis and Tissue Degeneration Program, David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA; BCMB Allied Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA; Corresponding author
Summary: MYC activates different metabolic programs in a cell-type- and cell-status-dependent manner. However, the role of MYC in inflammatory macrophages has not yet been determined. Metabolic and molecular analyses reveal that MYC, but not hypoxia inducible factor 1 (HIF1), is involved in enhancing early glycolytic flux during inflammatory macrophage polarization. Ablation of MYC decreases lactate production by regulating lactate dehydrogenase (LDH) activity and causes increased inflammatory cytokines by regulating interferon regulatory factor 4 (IRF4) in response to lipopolysaccharide. Moreover, myeloid-specific deletion of MYC and pharmacological inhibition of the MYC/LDH axis enhance inflammation and the bacterial clearance in vivo. These results elucidate the potential role of the MYC/LDH/IRF4 axis in inflammatory macrophages by connecting early glycolysis with inflammatory responses and suggest that modulating early glycolytic flux mediated by the MYC/LDH axis can be used to open avenues for the therapeutic modulation of macrophage polarization to fight against bacterial infection.
