{
  "abstract": "Introduction Iron is involved in central cellular processes including oxygen transport, while its uptake and storage are tightly regulated to avoid deficiency or excess. Labile (Fe2+) iron is the strongest oxidant in the human organism, inducing proinflammatory responses and the mesenchymal transition of cells in vitro. Iron is enriched in fibrotic tissue in preclinical models of liver, lung, kidney and heart fibrosis, while mice with iron overload spontaneously develop lung fibrosis. Moreover, iron chelation prevents or even reverts lung fibrosis in bleomycin models. While the potential pathogenic role of iron in Systemic Sclerosis (SSc) remains unknown, extravasation of erythrocytes that store 70% of total body iron, due to microvascular damage as depicted by capillaroscopy, could lead to hemorrhagic iron deposition in surrounding tissues. Herein, we explore the role of iron in profibrotic cellular transformation in SSc.Material and Methods We treated healthy and SSc-derived skin fibroblasts in vitro with i) iron & ii) the iron chelator deferiprone + TGF-b, to examine their effect on proinflammatory and profibrotic cell transformation. We analysed bulk RNA-seq of SSc skin to examine the potential enrichment of iron-related gene signatures and their association with profibrotic genes, as well as spatial RNA-seq data derived from SSc patients’ skin to examine the spatial distribution of iron enriched regions.Results In vitro treatment of skin fibroblasts increased the expression of proinflammatory / profibrotic genes including IL6 and SERPINE1. On the other hand, treatment with deferiprone ameliorated TGF-b-induced profibrotic cell transformation, even in the absence of exogenous iron administration. Gene Set Enrichment Analysis of RNA-seq from early diffuse SSc skin (GSE130955), revealed KRAS signaling, which is strongly associated with the presence of labile iron, as the most enriched pathway. Moreover, expression of the universal intracellular and extracellular protein that stores iron, namely ferritin (FTH1, FTL), was increased in SSc skin (1.5-fold, P<0.001) and positively correlated with the expression of profibrotic genes such as IL6, SERPINE1, ACTA2(aSMA) and COL1A1. Finally, re-analysis of spatial RNA-seq from SSc skin (GSE249279), revealed co-localization of FTH1/FTL with type I collagen, suggesting the enrichment of iron in fibrotic foci of SSc skin.Conclusions Iron promotes the proinflammatory and profibrotic transformation of cells and is enriched in the skin of patients with early SSc. Future studies are warranted to examine the potential pathogenic role of iron at different stages of SSc, as well as the value of iron chelators as anti-fibrotic agents.Acknowledgments This work is supported by FOREUM and Bodossaki foundation.",
  "authors": [
    {
      "affiliations": [
        "First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece"
      ],
      "name": "Nikolaos Vlachogiannis"
    },
    {
      "affiliations": [
        "First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece"
      ],
      "name": "Aikaterini Avdi"
    },
    {
      "affiliations": [
        "First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece"
      ],
      "name": "Kleio-Maria Verrou"
    },
    {
      "affiliations": [
        "Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom"
      ],
      "name": "Eleftherios Zormpas"
    },
    {
      "affiliations": [
        "First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece"
      ],
      "name": "Petros P Sfikakis"
    }
  ],
  "title": "P.015 A pathogenic role of microvasculopathy-related hemorrhagic deposition of iron in the skin: ex vivo results in systemic sclerosis",
  "uid": "b0bb38d4-a078-51f4-b129-d2b969337216"
}