Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization Journal Article
| Authors: | Xu, H.; Zhu, J.; Smith, S.; Foldi, J.; Zhao, B.; Chung, A. Y.; Outtz, H.; Kitajewski, J.; Shi, C.; Weber, S.; Saftig, P.; Li, Y.; Ozato, K.; Blobel, C. P.; Ivashkiv, L. B.; Hu, X. |
| Article Title: | Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization |
| 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. © 2012 Nature America, Inc. All rights reserved. |
| Keywords: | signal transduction; controlled study; unclassified drug; dna binding protein; dna-binding proteins; nonhuman; translation initiation; animal cell; mouse; animals; mice; inflammation; notch receptor; mice, inbred c57bl; inflammatory cell; immunoregulation; transcription factors; gene expression regulation; toll like receptor 4; protein synthesis; protein-serine-threonine kinases; receptors, notch; initiation factor 4e; cell polarity; innate immunity; gene induction; macrophage; macrophages; cell activation; protein kinase; polarization; listeriosis; listeria monocytogenes; toll-like receptor 4; interferon regulatory factors; immunoglobulin j recombination signal sequence-binding protein; macrophage activation; rbp j protein; interferon consensus sequence binding protein; interleukin 1 receptor associated kinase 2; mnk1 protein; interleukin-1 receptor-associated kinases |
| Journal Title: | Nature Immunology |
| Volume: | 13 |
| Issue: | 7 |
| ISSN: | 1529-2908 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2012-01-01 |
| Start Page: | 642 |
| End Page: | 650 |
| Language: | English |
| DOI: | 10.1038/ni.2304 |
| PUBMED: | 22610140 |
| PROVIDER: | scopus |
| PMCID: | PMC3513378 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 4" - "Export Date: 9 January 2013" - "CODEN: NIAMC" - "Source: Scopus" |
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