Fibroblasts are present in virtually all tissues of the human body. For a long time, their contribution to health and disease was largely underestimated. It is now well established that fibroblasts have functions extending far beyond the production and remodelling of the extracellular matrix (ECM).
They contribute to tissue homeostasis and play a central role in tissue repair and remodelling. In addition, fibroblasts regulate local immune responses by recruiting immune cells and modulating their activation. However, persistent or dysregulated fibroblast activation can promote chronic inflammation and excessive ECM deposition, ultimately leading to tissue damage and loss of organ function.
Our research focuses on the mechanisms underlying persistent fibroblast activation in rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic sclerosis (SSc, scleroderma). Although these diseases differ considerably in their clinical manifestations, fibroblasts play a central role in the pathogenesis of both. In RA, fibroblast-like synoviocytes contribute to synovial inflammation and the destruction of cartilage and bone. In SSc, aberrant activation of fibroblasts promotes excessive ECM production and progressive fibrosis of the skin and internal organs.
We aim to understand the molecular mechanisms that sustain fibroblast activation and determine their disease-associated functions. In particular, we investigate how inflammatory signaling pathways, cellular metabolism and interactions with other cell types, including immune cells, regulate fibroblast responses. Our research combines the analysis of human tissues with functional and mechanistic studies in primary human cells and three-dimensional cell and tissue models. We use a broad range of approaches, including transcriptomic analyses, advanced imaging techniques, and biochemical and metabolomic profiling.
A major goal of our research is to identify mechanisms that can be therapeutically targeted to suppress pathological fibroblast activation and thereby limit chronic inflammation and fibrosis.
On the left, an IHC picture showing FLS in a 3D synovial organ culture system. On the right, an IF picture showing FLS-T-cell interactions in vitro.
Publications Highlights
Cytokine-directed cellular cross-talk imprints synovial pathotypes in rheumatoid arthritis.
In this study we characterize T-cell-FLS interactions in the context of RA by using a high content imaging platform. We further show how distinct inflammatory cytokines specifically impact these interactions and translate our in-vitro findings in clinically relevant synovial pathotypes of RA.
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TNFR2 is critical for TNF-induced rheumatoid arthritis fibroblast-like synoviocyte inflammation.
Our work here demonstrates the crucial role of TNF-receptor 2 (TNFR2, TNFRSF1B) in FLS activation in the context of RA.
IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes.
Within this paper we establish a role for the transcription factor IRF1 in TNF-induced activation of RA-FLS. We further describe a TNF-IRF1-STAT1 signaling cascade that is important for FLS chemokine secretion.
mTOR Senses environmental cues to shape the fibroblast-like synoviocyte response to inflammation.
In this paper we show how the metabolic mTOR pathway senses and shapes the cellular response to inflammatory stimuli, such as TNF. We further show how the metabolic microenvironment impacts on the FLS response to inflammation via mTOR.