Senolytic treatment to rescue hallmarks of senescence in lymph node fibroblasts from patients with rheumatoid arthritis: Implications for premature aging and potential therapeutic intervention in early rheumatoid arthritis

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Cellular senescence, a state of proliferation arrest, is implicated in the pathogenesis of age-related diseases such as rheumatoid arthritis (RA). The pathogenesis of RA, characterized by immune dysregulation and systemic autoimmunity preceding clinical onset of disease, may involve early accumulation of senescent lymph node (LN) fibroblasts driving immune tolerance breakdown. This study aims to explore the hallmarks of senescence in LN fibroblasts during the earliest phases of RA and evaluate the effects of dasatinib. Human LN fibroblasts were isolated from inguinal LN needle biopsies from autoantibody-positive individuals at risk of developing RA (RA-risk individuals), RA patients, and seronegative healthy volunteers. Senescence hallmarks and the effects of dasatinib treatment were assessed using quantitative gene expression analysis, flow cytometry, microscopy, and live-cell imaging. Cell size, granularity, and autofluorescence were significantly greater in RA LN fibroblasts compared with controls. Altered gene expression of senescence-associated genes was observed in RA LN fibroblasts. Elevated senescence-associated β-galactosidase activity, more lipofuscin-positive granules, and DNA damage were observed in RA-risk and RA LN fibroblasts. Notably, RA(-risk) LN fibroblasts presented impaired DNA damage repair capacity. Dasatinib treatment significantly improved the size and ability of the LN fibroblast pool to repair DNA damage. We observed multiple senescence hallmarks in RA LN fibroblasts and, to a lesser extent, in RA-risk LN fibroblasts, which could be partially restored by senescent cell removal via dasatinib treatment. These findings suggest a role for senescent LN fibroblasts in RA pathogenesis and highlight the potential of dasatinib as a potential therapeutic intervention to mitigate senescence-associated defects in RA.

This publication has 54 references indexed in Scilit: