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

Xu, Haixia; Zhu, Jimmy; Smith, Sinead; Foldi, Julia; Zhao, Baohong; Chung, Andy; Outtz, Hasina H.; Kitajewski, Jan; Shi, Chao; Weber, Silvio; Säftig, Paul; Li, Yueming; Ozato, Keiko; Blobel, Carl P.; Ivashkiv, Lionel B.; Hu, Xiaoyu

doi:10.1038/ni.2304

Cited by 363 publications

(361 citation statements)

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“…Upon LPS stimulation, eIF4E can be activated via its phosphorylation at S209 by Mnk1/2 (10). The phosphorylated eIF4E then activates the translation of mRNA of inflammatory genes, including IRF8 (11,12). Interestingly, the translation of IκBα is also regulated by the phosphorylation and activation of eIF4E at S209 (13).…”

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Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Bao

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB-dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/ threonine-protein kinase 2 (Mknk2). Brd4-deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2-eIF4E pathway, Brd4 provides an additional layer of control for NF-κB-dependent inflammatory gene expression and inflammatory response.T he inducible transcription factor NF-κB plays a key role in regulating the inflammatory and immune responses in mammals (1, 2). The prototypical NF-κB complex, the heterodimer of p50 and RelA, is sequestered in the cytoplasm by its assembly with its inhibitor IκBα (1, 2). Upon stimulation, IκB kinase complex is activated and phosphorylates IκBα, leading to the degradation of IκBα, the nuclear translocation of NF-κB complex, and the activation of NF-κB target genes (1-3). Importantly, one of NF-κB target genes is its inhibitor, IκBα. The resynthesized IκBα enters the nucleus, where it removes the NF-κB from the DNA and terminates activated NF-κB (1, 2, 4). The resynthesis of IκBα therefore creates a negative feedback regulation of NF-κB signaling, preventing sustained NF-κB activation and prolonged inflammatory response.In addition to the negative feedback regulation from resynthesized IκBα, the NF-κB-mediated inflammatory response is subjected to many layers of regulation, including transcriptional, translational, and posttranslational regulation (5-8). Recent studies demonstrate that selective translational control of gene expression plays an important regulatory role in the inflammatory response (7, 9). The eukaryotic translation initiation factor eIF4E has been shown to be the node of the translational control of immune response via the mTOR signaling pathway or the MAPK-Mnk1-Mnk2-eIF4E pathway (9). Upon LPS stimulation, eIF4E can be activated via its phosphorylation at S209 by Mnk1/2 (10). The phosphorylated eIF4E then activates the translation of mRNA of inflammatory genes, including IRF8 (11, 12). Interestingly, the translation of IκBα is also regulated by the phosphorylation and activation of e...

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confidence: 99%

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Bao

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…3D). Interestingly, it has been described that IRF8 synthesis is controlled by RBP-J, suggesting a connection between NOTCH and TLR pathways [10]. …”

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“…The NOTCH-RBP-J pathway seems to control the expression of typical pro-inflammatory genes characteristic of M1-type macrophages, including and Nos2 [8,9], leading to a stronger immune response of these cells, mediated, in part, by increased NF-κB activity [4,5]. RBP-J also regulates the translation of IRF8, a key transcription factor for M1 differentiation [10].Delta-like protein-1 (DLK1) is an EGF-like protein that interacts with the NOTCH1 receptor through specific EGF-like repeats [11] and inhibits multiple NOTCH-mediated processes, such as adipogenesis or hematopoiesis [12][13][14][15]. DLK1 seems to function as a noncanonical NOTCH1 ligand, as it lacks the conserved DSL domain mediating classical NOTCH ligand-receptor interactions.…”

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DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages

González¹,

Ruiz-García²,

Monsalve³

et al. 2015

Eur J Immunol

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Delta-like protein 1 (DLK1) is a noncanonical ligand that inhibits NOTCH1 receptor activity and regulates multiple differentiation processes. In macrophages, NOTCH signaling increases TLR-induced expression of key pro-inflammatory mediators. We have investigated the role of DLK1 in macrophage activation and inflammation using Dlk1-deficient mice and Raw 264.7 cells overexpressing Dlk1. In the absence of Dlk1, NOTCH1 expression is increased and the activation of macrophages with TLR3 or TLR4 agonists leads to higher production of IFN-β and other pro-inflammatory cytokines, including TNF-α, IL-12, and IL-23. The expression of key proteins involved in IFN-β signaling, such as IRF3, IRF7, IRF1, or STAT1, as well as cRel, or RelB, which are responsible for the generation of IL-12 and IL-23, is enhanced in Dlk1 KO macrophages. Consistently, Dlk1 KO mice are more sensitive to LPS-induced endotoxic shock. These effects seem to be mediated through the modulation of NOTCH1 signaling. TLR4 activation reduces DLK1 expression, whereas increases NOTCH1 levels. In addition, DLK1 expression diminishes during differentiation of human U937 cells to macrophages. Overall, these results reveal a novel role for DLK1 as a regulator of NOTCH-mediated, pro-inflammatory macrophage activation, which could help to ensure a baseline level preventing constant tissue inflammation.Keywords: Cytokine r DLK1 r Inflammatory inhibitor r Macrophage r NOTCH signaling r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacrophages are key cells in innate and adaptive immune response to pathogens. Toll-like receptors (TLR) recognize conserved microbial structures and induce the activation of macrophages, thus increasing their phagocytic and cytotoxic activities, and leading to the production of inflammatory cytokines, Correspondence: Dr. María J. Ruiz-Hidalgo and Dr. María J. M. Díaz-Guerra e-mail: Maria.RHidalgo@uclm.es; MariaJose.Martinez@uclm.es such as TNF-α and IL-1, and cytokines of the IL-6 and IL-12 families, which regulate T-cell differentiation [1].Macrophages display a remarkable plasticity and can change their functioning in response to environmental signals, which allows a fine-tuning of their activity to adapt to different situations. Unrestrained activation of TLR responses can lead to excessive inflammation and tissue damage and contribute to the pathogenesis of inflammatory disorders, such as septic shock. Multiple mechanisms are implicated in the control of macrophage activation, including inhibitory cytokines, transcriptional repressors, and epigenetic modifications [2,3].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2616 María J. González et al. Eur. J. Immunol. 2015. 45: 2615-2627 In this line, a critical role for NOTCH signaling in macrophage activation and polarization has been evidenced [4][5][6]. Ligand binding to the NOTCH receptors triggers a two-step proteolytic cleavage causing the release of the NOTCH intracellular doma...

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“…A recent study has revealed that Notch2-regulated intestinal DCs produce IL-23 required for controlling Citrobacter rodentium (22). In addition to the development or differentiation of DCs, Notch plays an important role in the activation of DCs and macrophages (23,24 To reveal the involvement of Notch signaling in the development of CD11c + CX 3 CR1 + cells, Rbpj flox/flox mice were crossed with CD11c promoter-driven Cre transgenic (Rbpj −/− ) mice, and this strain was crossed further with Cx3cr1 knockin mice in which Cx3cr1 was replaced by GFP (7). (Hereafter, this strain is called "Rbpj −/− : CX 3 CR1 gfp/+ mice.")…”

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Differentiation of CD11c ⁺ CX ₃ CR1 ⁺ cells in the small intestine requires Notch signaling

Ishifune

Maruyama

Sasaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The gastrointestinal tract comes into direct contact with environmental agents, including bacteria, viruses, and foods. Intestinespecific subsets of immune cells maintain gut homeostasis by continuously sampling luminal antigens and maintaining immune tolerance. CD11c + CX 3 CR1 + cells sample luminal antigens in the small intestine and contribute to the trafficking of bacteria to lymph nodes under dysbiotic conditions. The molecular mechanisms crucial for the differentiation of CD11c

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

Cited by 363 publications

References 49 publications

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages

Differentiation of CD11c ⁺ CX ₃ CR1 ⁺ cells in the small intestine requires Notch signaling

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

Cited by 363 publications

References 49 publications

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR‐activated murine macrophages

Differentiation of CD11c + CX 3 CR1 + cells in the small intestine requires Notch signaling

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Differentiation of CD11c ⁺ CX ₃ CR1 ⁺ cells in the small intestine requires Notch signaling