Senescent cells in Giant Cell Arteritis have inflammatory phenotype participating in tissue injury via IL-6 dependent pathways

Abstract

AbstractObjectivesAge is the strongest risk factor of Giant Cell Arteritis (GCA), implying a possible pathogenetic role of cellular senescence. To address this question, we applied an established senescence specific multi-marker algorithm in tissue artery biopsies (TABs) of GCA patients.MethodsSeventy five positive TABs from GCA patients and 22 negative from patients with Polymyalgia Rheumatica (PMR) were retrospectively retrieved and analyzed. Senescent cells and their histologic origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype (SASP) by triple co-staining. GCA or PMR artery culture supernatants were applied to primary skin fibroblasts with or without IL-6 blocking agent to explore the induction of IL-6 associated cellular senescence.ResultsSenescent cells were mainly present in GCA arteries at higher proportion compared to PMR (9.50% vs 2.66% respectively, p<0.0001) and were mainly originated from fibroblasts, macrophages and endothelial cells. IL-6 was expressed by senescent fibroblasts and macrophages while MMP-9 by fibroblasts only. IL-6 positive senescent cells were associated with the extension of vascular inflammation (adventitial limited disease vs transmural inflammation: 10.02% vs 4.37% respectively, p<0.0001). GCA but not PMR artery culture supernatant could induce IL-6-associated senescence that was partially inhibited by IL-6 blockade.ConclusionsSenescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk. These findings might suggest a potential implication in disease pathogenesis by perpetuating inflammation and affecting vascular remodeling via IL-6 dependent mechanisms.