1. Academic Validation
  2. Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation

Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation

  • Cell Death Dis. 2021 Oct 27;12(11):1009. doi: 10.1038/s41419-021-04284-5.
Yanhong Shou  # 1 Lu Yang  # 1 Yongsheng Yang 2 Jinhua Xu 3 4
Affiliations

Affiliations

  • 1 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, P. R. China.
  • 2 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, P. R. China. yangyongsheng73512@126.com.
  • 3 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, P. R. China. jinhuaxu@fudan.edu.cn.
  • 4 Shanghai Institute of Dermatology, Shanghai, P. R. China. jinhuaxu@fudan.edu.cn.
  • # Contributed equally.
Abstract

Psoriasis is a common, chronic, and recurrent inflammatory disease. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes. Keratinocyte death is also involved in many pathophysiological conditions and amplifies the inflammatory cascade. As a newly recognized form of cell death, Ferroptosis is involved in several inflammatory diseases. In this study, we aimed to investigate a previously unrecognized role for Ferroptosis in psoriasis. Ferroptosis is mediated by lipid peroxidation and iron overload. Compared with normal lesions, the mRNA expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2), and Transferrin Receptor (TFRC) were highly expressed in psoriatic lesions, with decreased levels of Glutathione Peroxidase 4 (GPX4), ferritin LIGHT chain (FTL), and ferritin heavy chain 1 (FTH1). The protein levels of ACSL4 and GPX4 were consistent with their mRNA levels. A similar tendency of Ferroptosis was also observed in erastin-treated human primary keratinocytes and the Imiquimod (IMQ)-induced model of psoriasis. To investigate the correlation between inflammation and peroxidation, we analyzed single-cell RNA-sequencing data and identified 15 cell types. There was a high correlation between the activity of the lipid oxidation and the Th22/Th17 response in keratinocytes at a single-cell level. Moreover, ferrostatin-1 (Fer-1), a potent inhibitor of lipid peroxidation, suppressed ferroptosis-related changes in erastin-treated keratinocytes and alleviated psoriasiform dermatitis of IMQ-induced models. Additionally, Fer-1 blocked inflammatory responses in vitro and in vivo, reducing the production of cytokines including TNF-α, IL-6, IL-1α, IL-1β, IL-17, IL-22, and IL-23. This study revealed an expression pattern of Ferroptosis in which specific molecules enhance inflammatory reactions in psoriasis.

Figures
Products