Notch-1 Up-Regulation and Signaling following Macrophage Activation Modulates Gene Expression Patterns Known to Affect Antigen-Presenting Capacity and Cytotoxic Activity

Monsalve, Eva M.; Pérez, Miguel A.; Rubio, Antonio; Ruiz-Hidalgo, Marı́a José; Baladrón, Victoriano; Garcı́a-Ramı́rez, José J.; Gómez, Juan Carlos Escudero; Laborda, Jorge; Díaz-Guerra, María José

doi:10.4049/jimmunol.176.9.5362

Cited by 158 publications

(214 citation statements)

References 67 publications

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“…WT macrophages expressed moderate levels of Dlk1 as compared with other mouse cell types (data not shown, Fig. 1A and D), whereas the expression of Notch1, the main NOTCH receptor expressed in mouse macrophages [4], was significantly higher in Dlk1 KO macrophages (Fig. 1A).…”

Section: Dlk1 Modulates Notch1 Expression In Mouse Macrophagesmentioning

confidence: 84%

“…Peritoneal macrophages were isolated as previously described [4] from 2-month-old Dlk1 WT or KO male mice, 4 days after intraperitoneal injection of 2 ml 3% sterile thioglycollate broth (w/v in water, Gibco). Each batch of macrophages came from at least four mice of each genotype.…”

Section: Cells and Reagentsmentioning

confidence: 99%

“…This transcriptional activation complex drives the expression of NOTCH target genes, in particular the HES and HEY families of transcription factors [7]. 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].…”

Section: Introductionmentioning

confidence: 99%

“…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 domain (NICD) and its translocation to the nucleus, where it binds to the DNA-binding protein RBP-J/CSL/CBF1.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Dlk1 Modulates Notch1 Expression In Mouse Macrophagesmentioning

confidence: 84%

Section: Cells and Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

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“…Notch signaling effectuates important roles not only in the development of the immune system, but also critically in cell fate judgments among fully differentiated immune cells including macrophages or dendritic cells (11)(12)(13)(14). The Notch pathway is characterized by juxtacrine ligand-receptor interactions between adjacent cells, and macrophages are known * This work was supported by funds from the Indian Council of Medical Research (ICMR), the Department of Biotechnology (DBT); a collaborative grant (to the Indian Institute of Science and Karolinska Institute) from VINNOVA (The Swedish Governmental Agency for Innovation Systems) and DBT, India; the Department of Science and Technology (DST); and the Council for Scientific and Industrial Research (to K. N.…”

mentioning

confidence: 99%

Intracellular Pathogen Sensor NOD2 Programs Macrophages to Trigger Notch1 Activation

Bansal¹,

Balaji

2011

Journal of Biological Chemistry

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Another Notch in the Belt of Rheumatoid Arthritis

Zack,

Alzoubi,

Satoeya

et al. 2024

Arthritis & Rheumatology

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Notch ligands and receptors, including JAG1/2, DLL1/4, and Notch1/3, are enriched on macrophages (MΦs), fibroblast‐like synoviocytes (FLS), and/or endothelial cells in rheumatoid arthritis (RA) compared to normal synovial tissues (ST). Power Doppler ultrasound‐guided ST studies reveal that the Notch family is highly involved in early active RA, especially during neovascularization. In contrast, the Notch family is not implicated during the erosive stage, evidenced by their lack of correlation with radiographic damage in RA STs. TLRs and TNF are the common inducers of Notch expression in RA MΦs, FLS, and endothelial cells. Among Notch ligands, JAG1 and/or DLL4 are most inducible by inflammatory responses in RA MΦs or endothelial cells and trans‐activate their receptors on RA FLS. TNF plays a central role on Notch ligands, as anti‐TNF good responders display JAG1/2 and DLL1/4 transcriptional downregulation in RA ST myeloid cells. In in vitro studies, TNF increases Notch3 expression in MΦs, which is further amplified by RA FLS addition. Specific disease‐modifying anti‐rheumatic drugs (DMARDs) reduced JAG1 and Notch3 expression in MΦ and RA FLS cocultures. Organoids containing FLS and endothelial cells have increased expression of JAG1 and Notch3. Nonetheless, Methotrexate, IL‐6R antibodies, and B cell blockers are mostly ineffective at decreasing Notch family expression. NF‐κB, MAPK, and AKT pathways are involved in Notch signaling, whereas JAK/STATs are not. Although Notch blockade has been effective in RA preclinical studies, its small molecule inhibitors have failed in phase I and II studies, suggesting that alternative strategies may be required to intercept their function.image

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Notch-1 Up-Regulation and Signaling following Macrophage Activation Modulates Gene Expression Patterns Known to Affect Antigen-Presenting Capacity and Cytotoxic Activity

Cited by 158 publications

References 67 publications

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

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

Intracellular Pathogen Sensor NOD2 Programs Macrophages to Trigger Notch1 Activation

Another Notch in the Belt of Rheumatoid Arthritis

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