Skin hepcidin initiates psoriasiform skin inflammation via Fe-driven hyperproliferation and neutrophil recruitment

• Published in: Nature communications Vol. 15; no. 1; pp. 6718 - 14
• Main Authors: Abboud, Elise, Chrayteh, Doha, Boussetta, Nadia, Dalle, Héloise, Malerba, Mariangela, Wu, Ting-Di, Le Gall, Morgane, Reelfs, Olivier, Pourzand, Charareh, Mellett, Mark, Assan, Florence, Bachelez, Hervé, Poupon, Joël, Aractingi, Selim, Vaulont, Sophie, Sohier, Pierre, Oules, Bénédicte, Karim, Zoubida, Peyssonnaux, Carole
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 38/22; 38/39; 38/77; 45; 49/39; 49/91; 631/250/256; 631/443/319/1557; 631/45/321/1155; 64/60; 692/699/4033; Animal models; Animals; Cell Proliferation; Disease Models, Animal; Epidermis; Epidermis - metabolism; Epidermis - pathology; Female; Hepcidin; Hepcidins - genetics; Hepcidins - metabolism; Humanities and Social Sciences; Humans; Inflammation; Inflammation - metabolism; Inflammation - pathology; Iron; Iron - metabolism; Keratinocytes; Keratinocytes - metabolism; Leukocytes (neutrophilic); Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; multidisciplinary; Neutrophil Infiltration; Neutrophils; Pathogenesis; Psoriasis; Psoriasis - metabolism; Psoriasis - pathology; Remission; Science; Science (multidisciplinary); Skin - metabolism; Skin - pathology; Skin diseases; Skin lesions; Skin resistance; Transcriptomes; Transgenic mice
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50993-8

Psoriasis is a multifactorial, chronic inflammatory skin disease with unresolved questions on its primary events. Iron overload has been described in the epidermis of psoriasis patients, but its relevance remains unknown. We found that the key iron regulatory hormone hepcidin was highly expressed in the epidermis of psoriasis patients, especially the pustular variants resistant to treatments. In a murine model of acute skin inflammation, keratinocyte-derived hepcidin was required for iron retention in keratinocytes, leading to hyperproliferation of the epidermal layer and neutrophil recruitment, two main features of psoriatic skin lesions. Keratinocytes overexpressing hepcidin were sufficient to elicit these psoriasiform features in a transgenic mouse model. Furthermore, transcriptome analysis of these keratinocytes revealed canonical pathways found in human psoriasis, pointing to a causal role for hepcidin in the pathogenesis of the disease. Altogether, our data suggest that hepcidin could be an actionable target for skin psoriasis treatment, in addition to current therapeutics, or targeted as maintenance therapy during remission to prevent recurrence. The iron hormone, hepcidin is highly expressed in the skin of psoriasis patients. Here the authors show hepcidin is involved in the initiation of psoriasiform skin inflammation via iron-driven hyperproliferation of the epidermal layer and neutrophil recruitment.