Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization

Nat Immunol. 2012 May 20;13(7):642-50. doi: 10.1038/ni.2304.

Abstract

Emerging concepts suggest that the functional phenotype of macrophages is regulated by transcription factors that define alternative activation states. We found that RBP-J, the main nuclear transducer of signaling via Notch receptors, augmented Toll-like receptor 4 (TLR4)-induced expression of key mediators of classically activated M1 macrophages and thus of innate immune responses to Listeria monocytogenes. Notch-RBP-J signaling controlled expression of the transcription factor IRF8 that induced downstream M1 macrophage-associated genes. RBP-J promoted the synthesis of IRF8 protein by selectively augmenting kinase IRAK2-dependent signaling via TLR4 to the kinase MNK1 and downstream translation-initiation control through eIF4E. Our results define a signaling network in which signaling via Notch-RBP-J and TLRs is integrated at the level of synthesis of IRF8 protein and identify a mechanism by which heterologous signaling pathways can regulate the TLR-induced inflammatory polarization of macrophages.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Polarity / immunology
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Expression Regulation / immunology
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / immunology*
  • Inflammation / immunology*
  • Interferon Regulatory Factors / biosynthesis
  • Interferon Regulatory Factors / immunology*
  • Interleukin-1 Receptor-Associated Kinases / immunology
  • Listeriosis / immunology
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein-Serine-Threonine Kinases / immunology
  • Receptors, Notch / immunology*
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / immunology
  • Transcription Factors / metabolism

Substances

  • DNA-Binding Proteins
  • Elf4 protein, mouse
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Interferon Regulatory Factors
  • Rbpj protein, mouse
  • Receptors, Notch
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Transcription Factors
  • interferon regulatory factor-8
  • Mknk1 protein, mouse
  • Interleukin-1 Receptor-Associated Kinases
  • Protein-Serine-Threonine Kinases