Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis

Kisha Piggott, Jiusheng Deng, Kenneth Warrington, Brian Younge, Jessica T. Kubo, Manisha Desai, Jörg J. Goronzy, Cornelia M. Weyand

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Background- Giant cell arteritis is a granulomatous vasculitis of the aorta and its branches that causes blindness, stroke, and aortic aneurysm. CD4 T cells are key pathogenic regulators, instructed by vessel wall dendritic cells to differentiate into vasculitic T cells. The unique pathways driving this dendritic cell-T-cell interaction are incompletely understood, but may provide novel therapeutic targets for a disease in which the only established therapy is long-term treatment with high doses of corticosteroids. Methods and Results- Immunohistochemical and gene expression analyses of giant cell arteritis-affected temporal arteries revealed abundant expression of the NOTCH receptor and its ligands, Jagged1 and Delta1. Cleavage of the NOTCH intracellular domain in wall-infiltrating T cells indicated ongoing NOTCH pathway activation in large-vessel vasculitis. NOTCH activation did not occur in small-vessel vasculitis affecting branches of the vasa vasorum tree. We devised 2 strategies to block NOTCH pathway activation: γ-secretase inhibitor treatment, preventing nuclear translocation of the NOTCH intracellular domain, and competing for receptor-ligand interactions through excess soluble ligand, Jagged1-Fc. In a humanized mouse model, NOTCH pathway disruption had strong immunosuppressive effects, inhibiting T-cell activation in the early and established phases of vascular inflammation. NOTCH inhibition was particularly effective in downregulating Th17 responses, but also markedly suppressed Th1 responses. Conclusions- Blocking NOTCH signaling depleted T cells from the vascular infiltrates, implicating NOTCH- NOTCH ligand interactions in regulating T-cell retention and survival in vessel wall inflammation. Modulating the NOTCH signaling cascade emerges as a promising new strategy for immunosuppressive therapy of large-vessel vasculitis.

Original languageEnglish (US)
Pages (from-to)309-318
Number of pages10
JournalCirculation
Volume123
Issue number3
DOIs
StatePublished - Jan 25 2011

Keywords

  • NOTCH
  • T cell
  • arteries
  • costimulation
  • inflammation
  • interferon-γ
  • interleukin-17

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Piggott, K., Deng, J., Warrington, K., Younge, B., Kubo, J. T., Desai, M., Goronzy, J. J., & Weyand, C. M. (2011). Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis. Circulation, 123(3), 309-318. https://doi.org/10.1161/CIRCULATIONAHA.110.936203