Document Detail

Blocking the NOTCH pathway inhibits vascular inflammation in large-vessel vasculitis.
MedLine Citation:
PMID:  21220737     Owner:  NLM     Status:  MEDLINE    
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.
Kisha Piggott; Jiusheng Deng; Kenneth Warrington; Brian Younge; Jessica T Kubo; Manisha Desai; Jörg J Goronzy; Cornelia M Weyand
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-01-10
Journal Detail:
Title:  Circulation     Volume:  123     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-25     Completed Date:  2011-03-07     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  309-18     Citation Subset:  AIM; IM    
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MeSH Terms
Adoptive Transfer
Calcium-Binding Proteins* / antagonists & inhibitors,  genetics,  metabolism
Dendritic Cells / immunology
Dipeptides / pharmacology*
Down-Regulation / drug effects,  immunology
Giant Cell Arteritis* / drug therapy,  immunology,  metabolism
Intercellular Signaling Peptides and Proteins* / genetics,  metabolism
Interferon-gamma / metabolism
Interleukin-17 / metabolism
Intracellular Signaling Peptides and Proteins
Membrane Proteins / antagonists & inhibitors,  genetics,  metabolism*
Mice, SCID
Receptor, Notch1* / antagonists & inhibitors,  genetics,  metabolism
Signal Transduction / drug effects*,  immunology
Th1 Cells / drug effects,  immunology,  metabolism
Transplantation Chimera
Transplantation, Heterologous
Grant Support
AI57266/AI/NIAID NIH HHS; P01 HL058000/HL/NHLBI NIH HHS; P01 HL058000/HL/NHLBI NIH HHS; P01 HL058000-05/HL/NHLBI NIH HHS; R01 AI044142/AI/NIAID NIH HHS; R01 AI044142-10/AI/NIAID NIH HHS; R01 AI044142-11/AI/NIAID NIH HHS; R01 AI044142-12/AI/NIAID NIH HHS; R01 AI44142/AI/NIAID NIH HHS; R01 AR042527/AR/NIAMS NIH HHS; R01 AR042527-16/AR/NIAMS NIH HHS; R01 AR042527-17/AR/NIAMS NIH HHS; R01 AR042527-18/AR/NIAMS NIH HHS; R01 AR42527/AR/NIAMS NIH HHS; R01 EY011916/EY/NEI NIH HHS; R01 EY011916-11A1/EY/NEI NIH HHS; R01 EY011916-12/EY/NEI NIH HHS; R01 EY011916-13/EY/NEI NIH HHS; R01 EY011916-14/EY/NEI NIH HHS; R01 EY11916/EY/NEI NIH HHS; U19 AI057266/AI/NIAID NIH HHS; U19 AI057266-01/AI/NIAID NIH HHS
Reg. No./Substance:
0/Calcium-Binding Proteins; 0/Dipeptides; 0/Intercellular Signaling Peptides and Proteins; 0/Interleukin-17; 0/Intracellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; 0/Notch1 protein, mouse; 0/Receptor, Notch1; 0/delta protein; 134324-36-0/Serrate proteins; 82115-62-6/Interferon-gamma

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