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

• DOI: 10.1038/ni.2304
• Publication Date: 2012-05-20T17:05:11Z
• Authors: Haixia Xu; Jimmy Zhu; Sinead Smith; Julia Foldi; Baohong Zhao; Allen Y Chung; Hasina Outtz; Jan Kitajewski; Chao Shi; Silvio Weber; Paul Saftig; Yueming Li; Keiko Ozato; Carl P Blobel; Lionel B Ivashkiv; Xiaoyu Hu
• Keywords: IRF8; Hes3 signaling axis; IRF5; Macrophage polarization

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.