RESUMO
OBJECTIVES: Age 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 multimarker algorithm in temporal artery biopsies (TABs) of GCA patients. METHODS: 75(+) TABs from GCA patients, 22(-) TABs from polymyalgia rheumatica (PMR) patients and 10(-) TABs from non-GCA/non-PMR patients were retrospectively retrieved and analysed. Synovial tissue specimens from patients with inflammatory arthritis and aorta tissue were used as disease control samples. Senescent cells and their histological origin were identified with specific cellular markers; IL-6 and MMP-9 were investigated as components of the senescent associated secretory phenotype by triple costaining. GCA or PMR artery culture supernatants were applied to fibroblasts, HUVECs and monocytes with or without IL-6R blocking agent to explore the induction of IL-6-associated cellular senescence. RESULTS: Senescent cells were present in GCA arteries at higher proportion compared with 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 senescent fibroblasts only. IL-6(+) senescent cells were associated with the extension of vascular inflammation (transmural inflammation vs adventitia limited disease: 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-6R blockade. CONCLUSIONS: Senescent cells with inflammatory phenotype are present in GCA arteries and are associated with the tissue inflammatory bulk, suggesting a potential implication in disease pathogenesis.
Assuntos
Arterite de Células Gigantes , Polimialgia Reumática , Humanos , Arterite de Células Gigantes/complicações , Interleucina-6/genética , Metaloproteinase 9 da Matriz/genética , Células Endoteliais/metabolismo , Estudos Retrospectivos , Polimialgia Reumática/complicações , Fenótipo , Senescência Celular , Inflamação/complicaçõesRESUMO
OBJECTIVES: Giant Cell Arteritis-(GCA) is an inflammatory disease following a chronic, relapsing course. The metabolic alterations related to the intense inflammatory process during the active phase and to the rapid impact of steroid treatment, remain unknown. The study aims to investigate the serum metabolome in active and inactive disease state. METHODS: 110 serum samples from 50 patients [33-GCA and 17-Polymyalgia rheumatica-(PMR)] at 3 time points, 0-(V1: active disease), 1 and 6 months-(V2 and V3: remission) of treatment with glucocorticosteroids (GCs), were subjected to Nuclear Magnetic Resonance (NMR)-based metabolomic analysis. Multi- and univariate statistical analyses were utilized to unveil metabolome alterations following treatment. RESULTS: Distinct metabolic profiles were identified between activity and remission, independently to disease type. N-acetylglycoproteins and cholines of bound phospholipids, emerged as predictive markers of disease activity. Altered levels of 4 out of the 21 small molecules were also observed, including increased levels of phenylalanine, and decreased of glutamine, alanine, and creatinine in active disease. Metabolic fingerprinting discriminated GCA from PMR in remission. GCA and PMR patients exhibited characteristic lipid alterations as a response and/or adverse effect of GCs treatment. Correlation analysis showed that several identified biomarkers were further associated with acute phase reactants, C-Reactive Protein and Erythrocyte Sedimentation Rate. CONCLUSION: The NMR profile of serum metabolome could identify and propose sensitive biomarkers of inflammation. Metabolome alterations, following GCs treatment, could provide predictors for future steroid-induced side effects.
RESUMO
OBJECTIVES: To explore the presence of neutrophil extracellular traps (NETs) in inflamed temporal artery biopsies (TABs) of patients with GCA. METHODS: Ten patients with GCA [five with limited and five with associated generalized vascular involvement, as defined by 18F-fluorodeoxyglucose PET with CT (PET/CT)] and eight with PMR were studied. The presence, location, quantitation and decoration of NETs with IL-6, IL-1ß and IL-17A were assessed in TABs at the time of disease diagnosis by tissue immunofluorescence and confocal microscopy. Paired serum levels of IL-6 and IL-17A were also evaluated in all patients. RESULTS: All temporal artery biopsies from GCA, but not PMR, patients had NETs located mainly in the adventitia, adjacent to the vasa vasorum. NETs decorated with IL-6 were present in 8/10 TABs of GCA patients, of whom 5 were PET/CT(+) and 3 PET/CT(-) patients. IL-17A(+) NETs were observed in all GCA patients. IL-1ß(+) NETs were not detected in any GCA patient. No relation was found between serum IL-6 and IL-17A levels and NETs containing IL-6 and/or IL-17A. CONCLUSIONS: NETs bearing pro-inflammatory cytokines are present in inflamed GCA-TABs. Future studies with a larger number of patients from different centres will show whether the findings regarding neutrophils/NETs in the TAB are consistent and disclose their clinical impact.
Assuntos
Armadilhas Extracelulares , Arterite de Células Gigantes , Biópsia , Citocinas , Arterite de Células Gigantes/diagnóstico , Humanos , Interleucina-17 , Interleucina-6 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Artérias Temporais/diagnóstico por imagem , Artérias Temporais/patologiaRESUMO
Giant cell arteritis (GCA) is an autoimmune disease affecting large vessels in patients over 50 years old. It is an exemplary model of a classic inflammatory disorder with IL-6 playing the leading role. The main comorbidities that may appear acutely or chronically are vascular occlusion leading to blindness and thoracic aorta aneurysm formation, respectively. The tissue inflammatory bulk is expressed as acute or chronic delayed-type hypersensitivity reactions, the latter being apparent by giant cell formation. The activated monocytes/macrophages are associated with pronounced Th1 and Th17 responses. B-cells and neutrophils also participate in the inflammatory lesion. However, the exact order of appearance and mechanistic interactions between cells are hindered by the lack of cellular and molecular information from early disease stages and accurate experimental models. Recently, senescent cells and neutrophil extracellular traps have been described in tissue lesions. These structures can remain in tissues for a prolonged period, potentially favoring inflammatory responses and tissue remodeling. In this review, current advances in GCA pathogenesis are discussed in different inflammatory phases. Through the description of these-often overlapping-phases, cells, molecules, and small lipid mediators with pathogenetic potential are described.