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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/224308
Macrophage iron metabolism dysregulation in psoriasis
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[eng] Macrophages are the most plastic immune cells, representing the first line of defence after the physical barriers and acting as antigen-presenting cells to activate the adaptive immunity. They are present in the tissues at homeostatic conditions and, in case of infection or injury, their number increases by extravasation of circulating monocytes. Macrophage infiltration is a common feature of both acute and chronic inflammatory conditions. Psoriasis is a chronic autoimmune disease characterized by skin lesions and systemic manifestations. ZEB1 is a transcription factor and a key regulator of cell plasticity with roles from embryonic development to cancer progression. The role of ZEB1 in macrophages is now being characterized. It regulates the switch from a pro-inflammatory and immunogenic to an anti-inflammatory and tolerogenic phenotype. Our analysis of a published transcriptomics study indicates that ZEB1 expression is reduced in psoriasis-affected skin areas compared to unaffected regions and healthy controls skin.
These precedents led us to investigate the role of ZEB1 in macrophages in psoriasis. We found that mice lacking ZEB1 in their macrophages (𝑍𝑒𝑏1∆") exposed to a chemical model of psoriasis (imiquimod) exhibited worsening of skin (increased skin thickness and skin oxidative damage levels) and systemic (e.g., splenomegaly) inflammation. To characterize ZEB1 regulated transcriptome in this model, we conducted skin scRNA-seq and macrophage ATAC-seq of control and 𝑍𝑒𝑏1∆" mice, which revealed the upregulation of iron-related genes in 𝑍𝑒𝑏1∆" macrophages, subsequently supported by histological analysis. We also found that ZEB1 interacts with BACH1, a master transcriptional repressor of iron-related genes, and that this interaction is weakened in the context of the imiquimod treatment. The link between increased iron levels and macrophages function in skin microenvironment was supported by in vivo experiments, where skin macrophages and iron were depleted. Our results in mice were supported by data in psoriatic patients that exhibited increased iron and iron-related damage levels in the monocytes from peripheral blood compared to healthy controls. Altogether, our data show a role for ZEB1 in skin macrophages protecting against local and systemic inflammation in psoriasis through the repression of iron metabolism genes.
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BRISCHETTO, Agnese. Macrophage iron metabolism dysregulation in psoriasis. [consulta: 6 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/224308]