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

Elise Abboud; Doha Chrayteh; Nadia Boussetta; Héloise Dalle; Mariangela Malerba; Ting Di Wu; Morgane Le Gall; Olivier Reelfs; Charareh Pourzand; Mark Mellett; Florence Assan; Hervé Bachelez; Joël Poupon; Selim Aractingi; Sophie Vaulont; Pierre Sohier; Bénédicte Oules; Zoubida Karim; Carole Peyssonnaux

doi:10.1038/s41467-024-50993-8

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

Elise Abboud, Doha Chrayteh, Nadia Boussetta, Héloise Dalle, Mariangela Malerba, Ting Di Wu, Morgane Le Gall, Olivier Reelfs, Charareh Pourzand, Mark Mellett, Florence Assan, Hervé Bachelez, Joël Poupon, Selim Aractingi, Sophie Vaulont, Pierre Sohier, Bénédicte Oules, Zoubida Karim, Carole Peyssonnaux

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Abstract

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.

Original language	English
Article number	6718
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-50993-8
Publication status	Published - 7 Aug 2024

Data Availability Statement

Data supporting the findings of this study are available in the article, its Supplementary information, the source data file and from the corresponding author upon request. RNA-sequencing data have been deposited in the Gene Expression Omnibus (GEO) database under accession code GSE220993. Datasets used in Supplementary Fig. 1 are available at GEO, accession number GSE13355. Source data are provided with this paper.

Funding

The authors would like to greatly acknowledge the PIME (Alain Schmitt), GenomIC (Benjamin Saintpierre), HistIM and animal facilities of Institut Cochin. The authors thank Jacques Mathieu, Marion Falabregue, Jean-Christophe Deschemin, Sara Guegan, Romain Fontaine, Peter Kanaan and Elio Rivierre for scientific discussions and technical advice or help. This work was supported by fundings from the \u201CFondation pour la Recherche M\u00E9dicale\u201D DEQ20160334903, EQ202103012630, PMT202206015641 (C.Peyssonnaux), the Laboratory of Excellence GR-Ex, (ANR-11-LABX-0051), the program \u201CInvestissements d\u2019avenir\u201D of the French National Research Agency, reference ANR-11-IDEX-0005-02 (C.Peyssonnaux and S.V.), the IDEX emergence program of the University Paris Cit\u00E9 RM27J21IDXE7-PSOHEPC (C.P.), AREMPH (Association pour les ETudes Medicales et Pharmaceutiques) (S.A. and B.O.), the Swiss National Science Foundation (341 310030_201242) (M.M.) and the LEO Foundation (LF-OC-22-000968) (M.M.).

Funders	Funder number
Université Sorbonne Paris Cité
University Paris Cité RM27J21IDXE7-PSOHEPC
Association pour les ETudes Medicales et Pharmaceutiques
MEMOLIFE Laboratory of Excellence and Paris Sciences Lettres
LEO Fondet
Fondation pour la Recherche Médicale
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Swiss National Science Foundation	341 310030_201242
Fondation pour les Etudes et Recherches sur le Développement International	PMT202206015641, EQ202103012630, DEQ20160334903
French National Research Agency	ANR-11-IDEX-0005-02
FENS-Kavli Network of Excellence	ANR-11-LABX-0051
Leonard Foundation	LF-OC-22-000968

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-50993-8Licence: CC BY-NC-ND

s41467-024-50993-8Final published version, 4.64 MBLicence: CC BY-NC-ND

Cite this

Abboud, E., Chrayteh, D., Boussetta, N., Dalle, H., Malerba, M., Wu, T. D., Le Gall, M., Reelfs, O., Pourzand, C., Mellett, M., Assan, F., Bachelez, H., Poupon, J., Aractingi, S., Vaulont, S., Sohier, P., Oules, B., Karim, Z., & Peyssonnaux, C. (2024). Skin hepcidin initiates psoriasiform skin inflammation via Fe-driven hyperproliferation and neutrophil recruitment. Nature Communications, 15(1), Article 6718. https://doi.org/10.1038/s41467-024-50993-8

Abboud, E, Chrayteh, D, Boussetta, N, Dalle, H, Malerba, M, Wu, TD, Le Gall, M, Reelfs, O, Pourzand, C, Mellett, M, Assan, F, Bachelez, H, Poupon, J, Aractingi, S, Vaulont, S, Sohier, P, Oules, B, Karim, Z & Peyssonnaux, C 2024, 'Skin hepcidin initiates psoriasiform skin inflammation via Fe-driven hyperproliferation and neutrophil recruitment', Nature Communications, vol. 15, no. 1, 6718. https://doi.org/10.1038/s41467-024-50993-8

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title = "Skin hepcidin initiates psoriasiform skin inflammation via Fe-driven hyperproliferation and neutrophil recruitment",

abstract = "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.",

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AU - Abboud, Elise

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AU - Dalle, Héloise

AU - Malerba, Mariangela

AU - Wu, Ting Di

AU - Le Gall, Morgane

AU - Reelfs, Olivier

AU - Pourzand, Charareh

AU - Mellett, Mark

AU - Assan, Florence

AU - Bachelez, Hervé

AU - Poupon, Joël

AU - Aractingi, Selim

AU - Vaulont, Sophie

AU - Sohier, Pierre

AU - Oules, Bénédicte

AU - Karim, Zoubida

AU - Peyssonnaux, Carole

PY - 2024/8/7

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N2 - 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.

AB - 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.

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

Abstract

Data Availability Statement

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

UVA-Induced Iron Release and Sunscreen Protection

Mitochondrial and Lysosomal-Targeted Iron Chelators for the Monitoring and Adjustment of Cellular Labile Iron Pools

Cite this

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

Abstract

Data Availability Statement

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

UVA-Induced Iron Release and Sunscreen Protection

Mitochondrial and Lysosomal-Targeted Iron Chelators for the Monitoring and Adjustment of Cellular Labile Iron Pools

Cite this