Uncovering fibroblast diversity and functions in giant cell arteritis
Uncovering fibroblast diversity and functions in giant cell arteritis
Giant cell arteritis (GCA) is the most common form of systemic vasculitis in people over 50 years old. GCA is a large vessel vasculitis (LVV) and is characterized by granulomatous inflammation, vascular damage and remodeling. Fibroblasts are the predominant cell type of vascular adventitia, where the vasculitis process starts, however the knowledge about fibroblasts in GCA is very limited. In this thesis, we aimed to explore the phenotypes and functions of fibroblasts in GCA. In Chapter 2, we provided a comprehensive overview of the current knowledge on fibroblast pathobiology in LVV (mainly GCA and Takayasu arteritis). In Chapter 3, we identified different distribution patterns of fibroblast subtypes, cytokines related to remodeling and fibrosis in GCA-affected temporal arteries and aorta tissues. In Chapter 4, we documented decreased circulating fibroblast activation protein alpha (FAP) levels and elevated tissue FAP expression in patients with GCA. In Chapter 5, we established a coculture system of arterial fibroblasts and peripheral blood B cells. We found that activated B cells steer fibroblasts towards a pro-inflammatory phenotype but not myofibroblasts, and this effect can be abolished by blocking JAK-STAT signaling with baricitinib. In Chapter 6, we found that the interaction of fibroblasts and macrophages not only promotes the production of pro-inflammatory cytokines, growth factors and matrix metalloproteinases in fibroblasts, but also affects macrophage polarization. This interaction likely amplifies inflammation and damage in GCA tissues. In Chapter 7, the important role of fibroblasts in GCA was summarized and discussed.
Fibroblasts play an essential role in the pathogenesis of giant cell arteritis (GCA) by producing cytokines, chemokines, extracellular matrix, metalloproteinses, and interacting with immune cells. Pathological fibroblast may be a novel target for GCA treatment and vascular healing.