Fibroblast subsets dictate the stromal set-point in the synovium to influence the outcome of joint inflammation

Marsh, Lucy-Jayne (2025). Fibroblast subsets dictate the stromal set-point in the synovium to influence the outcome of joint inflammation. University of Birmingham. Ph.D.

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Abstract

Fibroblast subsets cause inflammation and damage. While their diversity and pathogenicity in arthritis are understood, little is known about how this fibroblast landscape is remodelled during the course of arthritis. This thesis explored the role of fibroblast population in joint inflammation.

I performed a temporal analysis of fibroblasts at the single cell resolution in spontaneously resolving models of inflammatory arthritis. During inflammatory phases, I identified an enrichment in Wnt signalling in synovial fibroblasts. In particular, WNT5A was associated with disease chronicity. Local administration of rWnt5a protein in mice undergoing inflammatory arthritis, lead to worsened disease severity through recruitment of pro-inflammatory macrophages and dendritic cells. In contrast, inhibition of Wnt signalling in mice with inflammation arthritis lead to
reduced joint swelling and leukocyte infiltration.

I also analysed fibroblasts during the resolving phase of arthritis, and identified a distinct subset of fibroblasts that exhibit a myofibroblast-like phenotype with a gene expression program linked to tissue repair. These fibroblasts express DKK3 (a member of the Dickkopf WNT Signalling Pathway Inhibitors with indeterminate biological function) and LRRC15 (a collagen binding protein), and show cross-talk with regulatory macrophages mediated by the TGF-β signalling pathway. In mice we observed that only these specific regulatory fibroblasts enhanced chromatin
accessibility, gene expression, and protein expression of DKK3 during resolution. Direct administration of rDKK3 reduced joint swelling and inflammation in mice, potentially by mediating polarisation of regulatory T Cells.

Together, the findings implicate Wnt signalling as a major driver of fibroblast-mediated inflammation and suggest that targeting the Wnt pathway could be a therapeutically relevant approach to rheumatoid arthritis, particularly in patients who do not respond to conventional treatments. We discovered regulatory fibroblasts that suppress inflammation and promote tissue repair by activating DKK3 signalling. These fibroblasts are activated during the resolution phase of inflammatory arthritis through cross-talk with MerTK+ macrophages. DKK3 secretion by these fibroblasts transforms the stromal landscape towards pro-repair phenotypes that control inflammation.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):