In Synergy With Interferon-γ, Interleukin-17 Activates Vascular Stromal Cells Toward a Proinflammatory Profile in...

This study investigated the role of interleukin-17 (IL-17) in giant cell arteritis (GCA), which has remained uncertain despite previous research suggesting a contribution of Th17 cells to the disease.

Temporal artery biopsies (TABs) were cultured ex vivo in MATRIGEL with IL-17, secukinumab, or control IgG and subsequently analyzed using bulk RNA-sequencing and real-time quantitative polymerase chain reaction. Positive TABs with GCA features were compared to negative TABs or used to obtain in vitro cultures of myofibroblasts (MFs). Confocal microscopy analyzed IL-17 receptor expression. MFs and peripheral blood mononuclear cells cocultures were used to study T cell polarization.

Transcriptomic analysis showed that secukinumab treatment of positive TABs reduced expression of genes linked to vascular inflammation, notably IL6. Real-time quantitative polymerase chain reaction analysis confirmed that secukinumab decreased messenger RNA encoding IL-6, CCL20, and granulocyte macrophage colony-stimulating factor (GM-CSF) in positive TABs, whereas IL-17 up-regulated them in negative TABs. No changes were observed regarding the expression of genes related to vascular remodeling. IL-17 receptor chains were expressed on MFs, and their expression was enhanced by interferon-γ (IFN-γ). Real-time quantitative polymerase chain reaction and Luminex analyses confirmed IL-17-driven upregulation of IL-6, CCL20, CCL2, GM-CSF, and vascular endothelial growth factor (VEGF) in MFs, which was reversed by secukinumab. Addition of IFN-γ to the culture increased the expression level of IL-17 receptor chains, resulting in a synergistic effect. Additionally, IL-17-pretreated MFs promoted Th17 polarization.

IL-17 exacerbates vascular inflammation in GCA by activating MFs and synergizing with IFN-γ to increase production of proinflammatory cytokines (IL-6, GM-CSF), chemokines (CCL20, CCL2), and angiogenic factors (VEGF), indicating that IL-17 is a key contributor to disease pathogenesis.