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 Article has an altmetric score of 13

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 1

Pro-ferroptotic epidermal oxPE signals in psoriasis are associated with decreased Gpx4 and increased 15-LOX-2 levels.

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Pro-ferroptotic epidermal oxPE signals in psoriasis are associated with ...
(A) Volcano plotof oxidized PE species (with 1–3 [O]) measured by LC-MS from pulmonary airway epithelium of patients with cystic fibrosis (CF) versus non-CF patients (red circles), from patient-matched psoriatic lesional versus control perilesional epidermis (blue circles), from bronchial epithelium of patients with severe asthma versus asthma-free patients (green circles), and from proximal and distal renal tubular epithelium of non-recovered versus recovered patients after acute kidney injury (AKI; purple circles). Ferroptosis-specific oxPE signals [PE(36:4)+2O, PE(36:5)+2O, PE(38:4)+2O] are indicated by stars. (B and C) Gene expression of ferroptosis markers and regulators in psoriatic versus patient-matched perilesional skin identified by the ferroptosis database FerrDb (B) or QIAGEN Ingenuity Pathway Analysis (C); n = 3. (D) Relative expression of Gpx4 in psoriatic and patient-matched nonlesional epidermis; n = 10. (E and F) Immunofluorescence (IF) images of psoriatic and perilesional skin (E) and mean fluorescence intensities (MFIs) per square micrometer of Gpx4 in basal/epibasal and spinous layers (F); n = 80 regions of interest (ROIs) per group, 3 patients. (G) Isolation of CD45–EGFR+CD104+CD49f+ basal KCs from human epidermis by FACS. (H) Relative Gpx4 expression in basal KCs isolated from psoriatic or control (nonlesional) epidermis as shown in G; n = 9. (I) Flow cytometry (top) and MFI (bottom) of Gpx4 in basal KCs from psoriatic versus control skin; n = 3. (J and K) IF images of psoriatic and perilesional skin (J) and 15-LOX-2 MFI per square micrometer in basal/epibasal and spinous layers (K); n = 54 ROIs per group, 3 patients. (L and M) IF images of psoriatic and perilesional skin (L) and oxBODIPY488/BODIPY546 (MFI/MFI) in basal/epibasal and spinous KCs (M); n = 21 ROIs per group, 3 patients. Dermal-epidermal junction is outlined in all IF images by white dashed lines. Data are means ± SD. Two-tailed Student’s t test (D, H, and I), 1-way ANOVA (F, K, and M); *P < 0.05. Scale bars: 50 μm.