[HTML][HTML] Notch–RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization

H Xu, J Zhu, S Smith, J Foldi, B Zhao, AY Chung… - Nature …, 2012 - nature.com
H Xu, J Zhu, S Smith, J Foldi, B Zhao, AY Chung, H Outtz, J Kitajewski, C Shi, S Weber…
Nature immunology, 2012nature.com
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 …
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.
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