Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease
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
- Joseph M. Pilewski (ORCID: https://orcid.org/0000-0002-0893-1155)
- Uma Chandran (ORCID: https://orcid.org/0000-0002-0817-9880)
- Svetlana N. Samovich (ORCID: https://orcid.org/0000-0001-5731-122X)
- Oleg Kruglov (ORCID: https://orcid.org/0000-0002-9847-7581)
- Louis J. Sparvero (ORCID: https://orcid.org/0000-0001-6347-8448)
- Yuri L. Bunimovich (ORCID: https://orcid.org/0000-0002-7920-8781)
- Alicia R. Mathers (ORCID: https://orcid.org/0000-0001-6931-8605)
- John A. Kellum (ORCID: https://orcid.org/0000-0003-1995-2653)
- Jiying Zhang (ORCID: https://orcid.org/0000-0002-4344-9794)
- Felicia M. Green (ORCID: https://orcid.org/0000-0002-9444-2701)
- Vrusha K. Shah (ORCID: https://orcid.org/0000-0002-2230-1811)
- Natalie Murray
- Hua Tian (ORCID: https://orcid.org/0000-0002-3598-0219)
- Vladimir A. Tyurin (ORCID: https://orcid.org/0000-0002-3474-1697)
- Ansuman Chattopadhyay (ORCID: https://orcid.org/0000-0002-5412-3749)
- Kavita Vats (ORCID: https://orcid.org/0000-0002-1491-348X)
- Valerian E. Kagan (ORCID: https://orcid.org/0000-0002-7245-1885)
- Yulia Y. Tyurina (ORCID: https://orcid.org/0000-0003-0287-2091)
- Alexander Chang (ORCID: https://orcid.org/0000-0002-3822-0469)
- Hülya Bayιr (ORCID: https://orcid.org/0000-0003-1174-3785)
- Sally E. Wenzel (ORCID: https://orcid.org/0000-0001-7761-9109)
- Kunal Singh
- Jiefei Wang
Institutions
- University of Pittsburgh (US)
- Columbia University Irving Medical Center (US)
- Association of Research Libraries (US)
- Rosalind Franklin Institute (GB)
- Indiana University School of Medicine
- Columbia University (US)
- University of Health Sciences Antigua (AG)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1172/jci183219
- Citations
- 17
- Primary Topic
- Psoriasis: Treatment and Pathogenesis
- Type
- article
- Field-Weighted Citation Impact
- 4.09
Funders
- National Psoriasis Foundation
- Engineering and Physical Sciences Research Council
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke
- National Institute of Arthritis and Musculoskeletal and Skin Diseases