Objectives This study investigated the role of IL‐17 in Giant Cell Arteritis (GCA), which has remained uncertain despite previous research suggesting a contribution of Th17 cells to the disease. Methods 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 RT‐qPCR. 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 co‐cultures were used to study T‐cell polarization. Results Transcriptomic analysis showed that secukinumab treatment of positive TABs reduced expression of genes linked to vascular inflammation, notably IL6 . RT‐qPCR analysis confirmed that secukinumab decreased mRNA encoding IL‐6, CCL20, and GM‐CSF in positive‐TABs, while IL‐17 upregulated 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 IFN‐γ. RT‐qPCR and Luminex® analyses confirmed IL‐17‐driven upregulation of IL‐6, CCL20, CCL2, GM‐CSF, and 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 pre‐treated MFs promoted Th17 polarization. Conclusions IL‐17 exacerbates vascular inflammation in GCA by activating MFs and synergizing with IFN‐γ to increase production of pro‐inflammatory cytokines (IL‐6, GM‐CSF), chemokines (CCL20, CCL2), and angiogenic factors (VEGF, indicating that IL‐17 is a key contributor to disease pathogenesis.

image