Notch-RBP-J Signaling Regulates the Transcription Factor IRF8 to Promote Inflammatory Macrophage Polarization

Overview

Journal Nat Immunol

Date 2012 May 22

PMID 22610140

Citations 226

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

Affiliations

Soon will be listed here.

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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