Chronic venous insufficiency (CVI) is characterized by valve dysfunction and venous hypertension, leading to erythrocytes’ extravasation into the tissue over time. CVI patients present dermal manifestations as; hyperpigmentation of the leg due to iron accumulation, histological changes regarding the dermal layer and fat (lipodermatosclerosis), and a high risk of developing a leg ulcer. For decades, researchers have studied CVI, and chronic venous ulcer (CVU) and iron have been considered critical pathological factors in this context, especially concerning oxidative stress and ROS formation. However, a clear understanding of the pathogenic effects of iron on the tissue network and the cross-talk of resident immune and skin tissue cells in the course of CVI is still missing. Therefore, in this project, we aim to investigate the pathological effect of iron overload on the cross-talk of resident immune and tissue cells in the skin.
In the current thesis work, biopsies from CVI patients were analysed. Immunohistochemistry (IHC) and spectrometric assay confirmed a massive iron accumulation in their dermis and hypodermis.
To dissect the different skin cells’ responses to iron overload, in vitro techniques were exploited. Mimic the erythrocyte overload in a macrophage (M2-like) culture revealed a shift in the gene signature towards inflammatory activation states of these cells. Hence, cytokine analysis confirmed an evident pro-inflammatory activation of macrophages (Ma). A mouse model with skin iron overload was generated to investigate the effect of iron overload in a more complex picture. Here, it was confirmed that iron induces an expansion of immune cells and a pro-inflammatory activation in the skin with a shift in resident macrophage subtypes, which was coupled to the adipose layer. Indeed, the dWAT of these mice shirked and showed clear signs of lipolysis. Moreover, IHC and IF staining of iron-mice skin showed increased cellularity of the lower dermis, which was linked to an expansion of the fibroblast population (dermis and stromal vascular fraction of the dWAT). Consistent with in vitro data, ECM genes were downregulated in the dermis, which may explain changes in the skin architecture of these mice.
In this thesis, the newly established mouse model made it possible to understand how iron may affect skin cells in CVI patients and can be extremely useful for future research to develop a new therapeutic approach. This work wants to highlight the significance of iron overload in the skin, which affects cellular cross-talk, altering skin homeostasis and possibly leading to an ulcer.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:88880 |
| Date | 05 January 2024 |
| Creators | Torregrossa, Marta |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/acceptedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | https://doi.org/10.1515/hsz-2021-0145, https://portal.issn.org/resource/ISSN/1437-4315 |
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