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Polyzou, A.

Publications and source records attributed to Polyzou, A..

3 recordsLinked to original sources
bioRxiv2023

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

ObjectivesAge 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.

cell biology↗
bioRxiv2020

ADA2 is a lysosomal DNase regulating the type-I interferon response

Deficiency of adenosine deaminase 2 (DADA2) is a severe, congenital syndrome, which manifests with hematologic, immunologic and inflammatory pathologies. DADA2 is caused by biallelic mutations in ADA2, but the function of ADA2, and the mechanistic link between ADA2 deficiency and the severe inflammatory phenotype remains unclear. Here, we show that monocyte-derived proteomes from DADA2 patients are highly enriched in interferon response proteins. Using immunohistochemistry and detailed glycan analysis we demonstrate that ADA2 is post-translationally modified for sorting to the lysosomes. At acidic, lysosomal pH, ADA2 acts as a novel DNase that degrades cGAS/Sting-activating ligands. Furthermore, we define a clear structure-function relationship for this acidic DNase activity. Deletion of ADA2 increased the production of cGAMP and type I interferons upon exposure to dsDNA, which was reverted by ADA2 overexpression or deletion of STING. Our results identify a new level of control in the nucleic acid sensing machinery and provide a mechanistic explanation for the pathophysiology of autoinflammation in DADA2. One Sentence SummaryADA2 is a lysosomal nuclease controlling nucleic acid sensing and type I interferon production.

immunology↗