The relationship between senescence and autophagy in human inflamed joint cell populations

Gauthier, Vincent (2024). The relationship between senescence and autophagy in human inflamed joint cell populations. University of Birmingham. Ph.D.

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Abstract

Rheumatoid arthritis (RA) and osteoarthritis (OA) are both diseases of the articular joint affecting the synovium. The synovium is critical to maintain joint homeostasis by protecting the articular cartilage and secreting synovial fluid. In OA and RA, the synovial lining layer (LL) and sub-lining (SL) are challenged by many stressors such as inflammation. Although RA and OA have different origins, age is a relevant factor for both. However, the role of aging in the degenerative processes occurring in the synovium remain poorly understood. By using multiplex immunofluorescence and spectral flow cytometry, we investigated aging through the perspective of cellular senescence, DNA damage and autophagy regulation via TFEB in the fibroblasts, tissue resident macrophages (TRMs), lymphocytes and endothelial cells (ECs) in OA and RA. We found that the lining layer is highly affected by DNA damage, up regulated p53 and accumulation of p16+ cells in both diseases. Notably, the LL fibroblasts have a higher DNA damage response o activation and senescence compared to the SL populations. Other cell types such as ECs also up regulated the DNA damage response through p21 and p53 expression. This pro damage context promotes the master regulator of autophagy TFEB. We found that TFEB activity and expression is decreased in OA compared to RA specifically in the LL fibroblasts. Together, these data provide the first map of the cellular stressors involved in inflamed synovium, paving the way to promising new regulation involving autophagy, metabolism, inflammation and cellular senescence in arthritis.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):