LB1775 Enlightening the role of iron overload in the development of cutaneous lipodermatosclerosis

Our study aims to investigate the pathogenic effects of iron overload in the skin of patients with chronic venous insufficiency (CVI), focusing on the underlying molecular mechanisms contributing to disease progression. While previous studies have examined the clinical aspects of CVI and lipodermatosclerosis (LDS), the molecular impact of iron on skin cells leading to LDS remain unclear. To address this gap, we employed in vitro and in vivo approaches. In biopsies from CVI patients, erythrocytes were observed in the dermis and hypodermis, along with siderophages (macrophages phagocyting erythrocytes), indicating a role of macrophages in erythrocyte clearance. We then demonstrated, that macrophages exposed to erythrocytes and iron in long-term acquire a pro-inflammatory phenotype, resulting in an inflammatory state in the skin. To investigate the effects of iron overload in vivo, we generated a mouse model that mimicked the local iron overload in skin as observed in CVI patients. The model exhibited an iron-overloaded adipose layer and adipocyte lipolysis, leading to adipocytes’ activation and release of adipokines, inflammatory cytokines, and chemokines. These events result in the recruitment of monocytes and macrophages with an inflammatory phenotype. We also observed reduced adipocyte differentiation and number, likely due to repression of Wnt signaling, downregulation of pro-differentiation and pro-adipogenesis genes and a decrease in adipose stem cells in the iron overloaded skin tissue. Moreover, the inflammatory state propagated into the dermis, resulting in resident macrophage activation, fibroblast hyperproliferation and reduced extracellular matrix deposition. In summary, this study provides insights into the molecular mechanisms underlying LDS progression in CVI patients with iron overload. Our findings suggest that iron overload in the skin induces an inflammatory state that originates in the adipose layer and propagates to the dermis, affecting resident macrophages, adipocytes and fibroblasts' activation and phenotype.