IRF5 and IRF5 Disease-Risk Variants Increase Glycolysis and Human M1 Macrophage Polarization by Regulating Proximal Signaling and Akt2 Activation

Cell Rep. 2016 Aug 30;16(9):2442-55. doi: 10.1016/j.celrep.2016.07.060. Epub 2016 Aug 18.

Abstract

Interferon regulatory factor 5 (IRF5) regulates inflammatory M1 macrophage polarization, and disease-associated IRF5 genetic variants regulate pattern-recognition-receptor (PRR)-induced cytokines. PRR-stimulated macrophages and M1 macrophages exhibit enhanced glycolysis, a central mediator of inflammation. We find that IRF5 is needed for PRR-enhanced glycolysis in human macrophages and in mice in vivo. Upon stimulation of the PRR nucleotide binding oligomerization domain containing 2 (NOD2) in human macrophages, IRF5 binds RIP2, IRAK1, and TRAF6. IRF5, in turn, is required for optimal Akt2 activation, which increases expression of glycolytic pathway genes and HIF1A as well as pro-inflammatory cytokines and M1 polarization. Furthermore, pro-inflammatory cytokines and glycolytic pathways co-regulate each other. Rs2004640/rs2280714 TT/TT IRF5 disease-risk-carrier cells demonstrate increased IRF5 expression and increased PRR-induced Akt2 activation, glycolysis, pro-inflammatory cytokines, and M1 polarization relative to GG/CC carrier macrophages. Our findings identify that IRF5 disease-associated polymorphisms regulate diverse immunological and metabolic outcomes and provide further insight into mechanisms contributing to the increasingly recognized important role for glycolysis in inflammation.

MeSH terms

  • Acetylmuramyl-Alanyl-Isoglutamine / pharmacology
  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Cell Differentiation
  • Gene Expression Regulation
  • Glycolysis / drug effects
  • Glycolysis / genetics*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Interferon Regulatory Factors / deficiency
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / metabolism
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation*
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism
  • Primary Cell Culture
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism

Substances

  • Adjuvants, Immunologic
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • IRF5 protein, human
  • Interferon Regulatory Factors
  • Intracellular Signaling Peptides and Proteins
  • Irf5 protein, mouse
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • TNF Receptor-Associated Factor 6
  • Tifab protein, human
  • Acetylmuramyl-Alanyl-Isoglutamine
  • AKT2 protein, human
  • IRAK1 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Proto-Oncogene Proteins c-akt
  • RIPK2 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinase 2