The traditional view of fibroblasts as the structural only framework of human tissue has changed considerably by discovering their active roles in shaping tissue microenvironment in health and disease. Pathogenic fibroblasts represent key drivers of chronic inflammation, fibrosis and tissue damage; fibroblast-targeting strategies, however, remain scarce. In PhD thesis, we investigate novel treatment strategies to suppress pathogenic fibroblast behaviours in inflammation and fibrosis. We specifically focus on pro-inflammatory synovial fibroblasts in rheumatoid arthritis (RA) – a prototypic inflammatory disease – and on pro-fibrotic skin fibroblasts in systemic sclerosis (SSc) - a prototypic fibrotic disease. Our studies of human synovium and cultured synovial fibroblasts infer that synovial fibroblasts represent an important therapeutic cell target of JAK inhibitors. We show that therapeutic concentrations of JAK inhibitor tofacitinib significantly decrease pro-inflammatory activities of cultured synovial fibroblasts, albeit not reaching the complete suppression. Thus, JAK inhibitors might interfere with stromal cell activation providing broad targeting across heterogenous synovial pathotypes. Furthermore, the acute tofacitinib withdrawal increases the pSTAT1/3 phosphorylation in synovial fibroblasts, providing a possible mechanistic explanation for acute arthritis worsening upon temporary interruption of tofacitinib therapy. Our research of skin fibrosis unravels a global metabolic dysregulation in the activated skin fibroblasts. We identify a new metabolism-targeting strategy to suppress pro-fibrotic activation of skin fibroblasts. Specifically, the metabolic intermediate dimethyl alpha-ketoglutarate effectively suppresses the pro-inflammatory/fibrotic activities of skin fibroblast in different 2D and 3D in vitro models. Furthermore, in a proof-of-concept study, we uncover the potent anti-fibrotic actions of dm-akg in the ex vivo explanted SSc skin tissue. These findings deduct that dm-akg-regulated cellular pathways might represent new therapeutic targets to combat skin fibrosis in SSc. Our research deepens the current understanding of fibroblast pathology in inflammation and fibrosis, and paves the way toward closing the gap in fibroblast therapeutic targeting in autoimmune diseases and beyond.
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