Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease
Kavita Vats, … , Valerian E. Kagan, Yuri L. Bunimovich
Kavita Vats, … , Valerian E. Kagan, Yuri L. Bunimovich
Published November 21, 2024
Citation Information: J Clin Invest. 2025;135(2):e183219. https://doi.org/10.1172/JCI183219.
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Research Article Dermatology Inflammation

Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease

Abstract

Dysregulations of epithelial-immune interactions frequently culminate in chronic inflammatory diseases of the skin, lungs, kidneys, and gastrointestinal tract. Yet, the intraepithelial processes that initiate and perpetuate inflammation in these organs are poorly understood. Here, by utilizing redox lipidomics we identified ferroptosis-associated peroxidation of polyunsaturated phosphatidylethanolamines in the epithelia of patients with asthma, cystic fibrosis, psoriasis, and renal failure. Focusing on psoriasis as a disease model, we used high-resolution mass spectrometry imaging and identified keratin 14–expressing (K14-expressing) keratinocytes executing a ferroptotic death program in human psoriatic skin. Psoriatic phenotype with characteristic Th1/Th17 skin and extracutaneous immune responses was initiated and maintained in a murine model designed to actuate ferroptosis in a fraction of K14+ glutathione peroxidase 4–deficient (Gpx4-deficient) epidermal keratinocytes. Importantly, an antiferroptotic agent, liproxstatin-1, was as effective as clinically relevant biological IL-12/IL-23/TNF-α–targeting therapies or the depletion of T cells in completely abrogating molecular, biochemical, and morphological features of psoriasis. As ferroptosis in select epidermal keratinocytes triggers and sustains a pathological psoriatic multiorgan inflammatory circuit, we suggest that strategies targeting ferroptosis or its causes may be effective in preventing or ameliorating a variety of chronic inflammatory diseases.

Authors

Kavita Vats, Hua Tian, Kunal Singh, Yulia Y. Tyurina, Louis J. Sparvero, Vladimir A. Tyurin, Oleg Kruglov, Alexander Chang, Jiefei Wang, Felicia Green, Svetlana N. Samovich, Jiying Zhang, Ansuman Chattopadhyay, Natalie Murray, Vrusha K. Shah, Alicia R. Mathers, Uma R. Chandran, Joseph M. Pilewski, John A. Kellum, Sally E. Wenzel, Hülya Bayır, Valerian E. Kagan, Yuri L. Bunimovich

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Figure 6

Psoriasiform inflammatory phenotype of K14/Gpx4 model responds to anti–IL-12/IL-23/TNF-α and anti-ferroptosis therapies.

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Psoriasiform inflammatory phenotype of K14/Gpx4 model responds to anti–I...
(A) Severity scores of K14/Gpx4 mice treated with anti–IL-12p40, anti–IL-23p19, or anti–TNF-α antibodies or IgG1/IgG2a isotype control antibodies, in conjunction with TMX; n = 6 mice per group, *P < 0.05 vs. vehicle control and respective isotype control. (B) Photographs of K14/Gpx4 mice treated with anti–IL-12p40 antibodies or isotype control antibodies on days 8 and 25 after TMX initiation. (C and D) Relative expression of IL-1β, IL-6, S100a8, IL-23, and TNF-α (RT-qPCR) (C) and percentages of immune cells (flow cytometry) (D) in skin of K14/Gpx4 mice treated with anti–IL-12p40, anti–IL-23p19, or anti–TNF-α antibodies or vehicle control 35 days after TMX initiation; n = 5 mice per group, *P < 0.05 vs. no-treatment control. (E) Severity scores of K14/Gpx4 mice treated with Lip-1 or vehicle control, in conjunction with TMX. Lip-1 was started on either day 2 (Lip-1A) or day 21 (Lip-1B); n = 5–6 mice per group, *P < 0.05 vs. control (days 3–34 for Lip-1A, days 25–34 for Lip-1B). (F) Photographs of K14/Gpx4 mice treated with Lip-1 or vehicle control. Shown are days 3 and 21 for Lip-1A and days 23 and 51 for Lip-1B after TMX initiation. (G and H) Relative expression of IL-1β, IL-6, S100a8, IL-23, TNF-α, IFN-γ, and IL-17A (RT-qPCR) (G) and percentages of immune cells (flow cytometry) (H) in skin of K14/Gpx4 mice treated with Lip-1A or vehicle control 35 days after TMX initiation; n = 5 mice per group, *P < 0.05 vs. control. Data are means ± SD. Two-way ANOVA (A and E), 1-way ANOVA (C and D), 2-tailed Student’s t test (G and H). Each dot in C, D, G, and H represents an individual mouse.