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
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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.
Nature Immunology 05/2012; 13(7):642-50. · 26.01 Impact Factor
