Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization Academic Article uri icon

Overview

MeSH Major

  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Inflammation
  • Interferon Regulatory Factors
  • Macrophages
  • Receptors, Notch

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 date

  • July 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3513378

Digital Object Identifier (DOI)

  • 10.1038/ni.2304

PubMed ID

  • 22610140

Additional Document Info

start page

  • 642

end page

  • 50

volume

  • 13

number

  • 7