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 5

K14/Gpx4 model recapitulates transcriptional profile of psoriasis.

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K14/Gpx4 model recapitulates transcriptional profile of psoriasis. (A) C...
(A) Comparison of DEGs (P < 0.05, |FC| > 1.5) in psoriatic skin (vs. patient-matched perilesional skin; n = 3 patients) with DEGs in K14/Gpx4 skin (vs. Cre– controls; n = 3 mice per group) using Illumina Correlation Engine. (B and C) Changes in the expression of ferroptosis-associated (B) and psoriasis-associated (C) genes (P < 0.05, |FC| > 1.5) in psoriatic versus patient-matched perilesional skin and K14/Gpx4 versus Cre– control mouse skin (18 days after TMX initiation). (D and E) Ingenuity Pathway Analysis (IPA) (D) and Gene Ontology (E) enrichment analyses using DEGs of psoriasis versus patient-matched perilesional skin and DEGs of K14/Gpx4 versus Cre– control mouse skin. (F) Pearson’s correlation coefficients from pairwise comparisons of transcriptional profiles of 3 human psoriasis datasets (including this study) and 5 mouse models of psoriasis (including K14/Gpx4) based on z scores of 19 psoriasis-associated pathways shown in D. (G and H) Correlation analyses of the overlapping DEGs between K14/Gpx4 model (vs. Cre– control) (G) or human psoriasis (lesional vs. patient-matched perilesional skin) (H) and select published studies on human psoriasis and murine models; Fisher’s exact test, Illumina Correlation Engine.