Senescence phenotype of lymph node stromal cells from patients with rheumatoid arthritis is partly restored by dasatinib treatment

Objective: Cellular senescence is a state of proliferation arrest of cells occurring during aging. The persistence and accumulation of senescent cells has been implicated in the pathogenesis of age-related diseases like rheumatoid arthritis (RA). RA is a chronic autoimmune disease in which loss of immune tolerance and systemic autoimmunity precedes clinical onset of disease. Lymph node stromal cells (LNSCs) are important regulators of immune tolerance. Accordingly, accumulating senescent LNSCs may potentially lead to defective immune tolerance and the development of systemic autoimmune disease. Methods: Human LNSCs were isolated and cultured from inguinal lymph node needle biopsies from individuals at risk of developing RA (RA-risk individuals), RA patients and seronegative healthy volunteers. Senescence hallmarks and the effect of dasatinib treatment were assessed using quantitative PCR, flow cytometry, microscopy and live-cell imaging. Results: Cell size, granularity and autofluorescence were significantly higher in RA LNSCs compared with control LNSCs. Stainings indicate more senescence associated β-galactosidase activity, more lipofuscin positive granules and increased DNA damage in RA-risk and RA LNSCs compared with control LNSCs. Moreover, we found altered gene expression levels of senescence associated genes in LNSCs from RA patients. Strikingly, the capacity to repair irradiation induced DNA damage was significantly lower in RA-risk and RA LNSCs compared with control LNSCs. Treating LNSCs with dasatinib significantly improved cell size and DNA repair capacity of cultured LNSCs. Conclusion: We observed multiple senescent hallmarks in RA LNSCs and to lesser extent already in RA-risk LNSCs, which could partly be restored by dasatinib treatment.