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.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA.
authors.forename: Haixia
authors.initials: H
authors.lastname: Xu
authors.forename: Jimmy
authors.initials: J
authors.lastname: Zhu
authors.forename: Sinead
authors.initials: S
authors.lastname: Smith
authors.forename: Julia
authors.initials: J
authors.lastname: Foldi
authors.forename: Baohong
authors.initials: B
authors.lastname: Zhao
authors.forename: Allen Y
authors.initials: AY
authors.lastname: Chung
authors.forename: Hasina
authors.initials: H
authors.lastname: Outtz
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
authors.forename: Chao
authors.initials: C
authors.lastname: Shi
authors.forename: Silvio
authors.initials: S
authors.lastname: Weber
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Yueming
authors.initials: Y
authors.lastname: Li
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000276:immunology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000276:immunology; D051880:Receptors, Notch / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D004268:DNA-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D050835:Interferon Regulatory Factors; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; D051880:Receptors, Notch; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; C491779:Elf4 protein, mouse; C497571:Rbpj protein, mouse; C493487:Tlr4 protein, mouse; C106281:Mknk1 protein, mouse