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Erschienen in: Angiogenesis 2/2024

05.10.2023 | Brief Communication

Notch ligands are biomarkers of anti-TNF response in RA patients

verfasst von: Stephanie R. Zack, Anja Meyer, Brian Zanotti, Michael V. Volin, Sania Deen, Neha Satoeya, Nadera Sweiss, Myles J. Lewis, Costantino Pitzalis, Jan K. Kitajewski, Shiva Shahrara

Erschienen in: Angiogenesis | Ausgabe 2/2024

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Abstract

Notch and its ligands play a critical role in rheumatoid arthritis (RA) pathogenesis. Hence, studies were conducted to delineate the functional significance of the Notch pathway in RA synovial tissue (ST) cells and the influence of RA therapies on their expression. Morphological studies reveal that JAG1, DLL4, and Notch1 are highly enriched in RA ST lining and sublining CD68+CD14+ MΦs. JAG1 and DLL4 transcription is jointly upregulated in RA MΦs reprogrammed by TLR4/5 ligation and TNF, whereas Syntenin-1 exposure expands JAG1, DLL4, and Notch1 expression levels in these cells. Single-cell RNA-seq data exhibit that JAG1 and Notch3 are overexpressed on all fibroblast-like synoviocyte (FLS) subpopulations, in parallel, JAG2, DLL1, and Notch1 expression levels are modest on RA FLS and are predominately potentiated by TLR4 ligation. Intriguingly, JAG1, DLL1/4, and Notch1/3 are presented on RA endothelial cells, and their expression is mutually reconfigured by TLR4/5 ligation in the endothelium. Synovial JAG1/JAG2/DLL1 or Notch1/3 transcriptomes were unchanged in patients who received disease-modifying anti-rheumatic drugs (DMARDs) or IL-6R Ab therapy regardless of disease activity score. Uniquely, RA MΦs and endothelial cells rewired by IL-6 displayed DLL4 transcriptional upregulation, and IL-6R antibody treatment disrupted RA ST DLL4 transcription in good responders compared to non-responders or moderate responders. Nevertheless, the JAG1/JAG2/DLL1/DLL4 transcriptome was diminished in anti-TNF good responders with myeloid pathotype and was unaltered in the fibroid pathotype except for DLL4. Taken together, our findings suggest that RA myeloid Notch ligands can serve as markers for anti-TNF responsiveness and trans-activate Notch receptors expressed on RA FLS and/or endothelial cells.
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Metadaten
Titel
Notch ligands are biomarkers of anti-TNF response in RA patients
verfasst von
Stephanie R. Zack
Anja Meyer
Brian Zanotti
Michael V. Volin
Sania Deen
Neha Satoeya
Nadera Sweiss
Myles J. Lewis
Costantino Pitzalis
Jan K. Kitajewski
Shiva Shahrara
Publikationsdatum
05.10.2023
Verlag
Springer Netherlands
Erschienen in
Angiogenesis / Ausgabe 2/2024
Print ISSN: 0969-6970
Elektronische ISSN: 1573-7209
DOI
https://doi.org/10.1007/s10456-023-09897-2

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