Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype
| Autor: | José L. Pablos, Cristina Municio, Alicia Usategui, Manuel J. Del Rey, Francisco J. Blanco, Sandra Ergueta, Gabriel Criado, Eduardo Martín, Alvaro Valin, Juan D. Cañete |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Senescence lcsh:Immunologic diseases. Allergy medicine.medical_specialty Aging Immunology CCL2 lcsh:Geriatrics medicine.disease_cause SASP Pathogenesis 03 medical and health sciences 0302 clinical medicine Synovitis Internal medicine medicine Interleukin 8 Rheumatoid arthritis Senolytic Synovial fibroblasts business.industry Research medicine.disease lcsh:RC952-954.6 030104 developmental biology Endocrinology Tumor necrosis factor alpha Cell senescence business lcsh:RC581-607 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Immunity & Ageing : I & A Immunity & Ageing, Vol 16, Iss 1, Pp 1-9 (2019) RUC. Repositorio da Universidade da Coruña instname |
| Popis: | BackgroundAccumulation of senescent cells has been associated with pro-inflammatory effects with deleterious consequences in different human diseases. The purpose of this study was to analyze cell senescence in human synovial tissues (ST), and its impact on the pro-inflammatory function of synovial fibroblasts (SF).ResultsThe expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal ST from variably aged donors. The proportion of p16(+) senescent cells in normal ST from older donors was higher than from younger ones. Although older RA and OA ST showed proportions of senescent cells similar to older normal ST, senescence was increased in younger RA ST compared to age-matched normal ST. The percentage of senescent SA-β-gal(+) SF after 14 days in culture positively correlated with donor’s age. Initial exposure to H2O2or TNFα enhanced SF senescence and increased mRNA expression ofIL6,CXCL8,CCL2andMMP3and proteins secretion. Senescent SF show a heightenedIL6,CXCL8andMMP3mRNA and IL-6 and IL-8 protein expression response upon further challenge with TNFα. Treatment of senescent SF with the senolytic drug fenofibrate normalizedIL6,CXCL8andCCL2mRNA expression.ConclusionsAccumulation of senescent cells in ST increases in normal aging and prematurely in RA patients. Senescence of cultured SF is accelerated upon exposure to TNFα or oxidative stress and may contribute to the pathogenesis of synovitis by increasing the production of pro-inflammatory mediators. |
| Databáze: | OpenAIRE |
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