123 Impact of local iron overload on crosstalk and phenotypes of immune and tissue cells in skin

This project focuses on elucidating the pathogenic effects of iron overload due to erythrocyte extravasation in skin immune-tissue cell crosstalk leading lipodermatosclerosis and leg ulcer patients with chronic venous insufficiency. We generated a new mice model local iron-overload skin, via ID-injection iron-dextran (Fedx). Prussian blue staining proved that accumulates dermis dWAT these mice, like patients’ skin. Skin Fedx shows signs lipodermatosclerosis; an increase total count (p=0.001) dermal layer, particularly F4/80+ macrophages (p=0.019) PDGFRa+ fibroblasts (p<0.001), accompanied less collagen deeper reduction size (p<0.001) adipocytes (p<0.001). Microscopic gene expression analysis highlight lipolysis, consequent lipids droplets (p=0.04), loss plin-1 (p=0.004) membrane, associated downregulation pro-adipogenic genes mice. FACS reveals shift Macrophage subtypes induction TNFa (p=0.0163) CD301b Relm-a (both p<0.001). Upregulation CCL2 (p=0.02), IL1ß, HMOX-1 (p=0.0001 dermis, p=0.01 dWAT) CCR2 (p=0.01) genes, indicate for pro-inflammatory activation compartment. Mechanistic human cells vitro erythrocyte-uptake induces ROS phenotype Macrophages. Fibroblasts response erythrocyte-fed resemble those phenotypes found The impact erythrocytes differentiation their Macrophages is ongoing. Our data suggest causes complex maintained inflammatory status proliferative fibrogenic fibroblasts, impaired adipogenesis, increased lipolysis.