Blocking the NOTCH Pathway Inhibits Vascular Inflammation in Large-Vessel Vasculitis

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: ␥-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

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

“…Notch ligation/inhibition promote changes in phenotype, cytokine and chemokine secretion, and Th polarization induced by cDCs and pDCs. Importantly, NotchNotch ligand interactions have been related to cellular infiltration in vascular inflammation (76), to secretion of proinflammatory cytokines in autoimmunity (69), and also to Kaposi sarcoma herpesvirus-associated suppression of genes related to cell cycle in adjacent endothelial cells (77). Additionally, Notch molecules may also be involved in communication between immune adjacent cells as shown between DCs and NK cells (50).…”

Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis

“…Adherent cell populations were >95% CD14 + by flow cytometry and were cultured in fresh complete medium supplemented with 50 ng/mL GM-CSF and 50 ng/mL IL-4 to generate monocyte-derived dendritic cells (MoDC), which were matured on day 6 with 100 ng/mL LPS or 100 U/mL IFN-γ. Laboratory and chimeras were generated as previously described (27). Normal human temporal or axillary arteries were engrafted subcutaneously into the back of the NSG mice.…”

“…To explore whether a defect in PD-L1 expression has impact on pathogenic immune functions in vasculitis, we made use of a human artery-NSG mouse model (27). In this model system, human axillary arteries are engrafted into NSG mice and PBMC from GCA patients or healthy individuals are adoptively transferred into the chimeras.…”

Selective up‐regulation of the soluble pattern‐recognition receptor pentraxin 3 and of vascular endothelial growth factor in giant cell arteritis: Relevance for recent optic nerve ischemia

“…Intimal hyperplasia is the consequence of many steps, including the interaction of dendritic cells with T cells, IFN␥-mediated macrophage activation, and growth factor synthesis. Little is known about the role of microenvironmental signals in shaping vascular involvement, although there is evidence that they regulate recruitment and local activation of T cells (33,34). Intimal hyperplasia and neovessel formation may depend on in situ vascular endothelial growth factor (VEGF) expression (35).…”