Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation

Yanhong Shou,Yanhong Shou,Lu Yang,Lu Yang,Yongsheng Yang,Jinhua Xu,Jinhua Xu,Jinhua Xu

doi:10.1038/s41419-021-04284-5

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.

Highlights

Psoriasis is a common, chronic autoimmune skin disease
Due to its role in inflammation and tissue damage, the epidermis, whereas in the psoriasis skin, glutathione peroxidase 4 (GPX4) was barely ferroptosis has been reported in different diseases including nervous expressed
The lipid oxidation pathway was significantly upregulated in the four cell populations of keratinocytes from psoriasis samples (Fig. 2E). These results revealed an enhancement of lipid peroxidation during psoriasis at the single-cell level

Summary

INTRODUCTION

It is characterized by the modification of the epidermis as a result of hyperproliferation of keratinocytes, excessive infiltration of immune cells, and accumulation of inflammatory cytokines [1]. Due to its role in inflammation and tissue damage, the epidermis, whereas in the psoriasis skin, GPX4 was barely ferroptosis has been reported in different diseases including nervous expressed. Western blot promotes cell death and potentiates a series of indicated the expression of ACSL4 and GPX4 in these skin tissues inflammatory reactions through the release of DAMPs and alarmins paralleled the appearance of the transcription expression levels. The To further confirm the results of ferroptosis-related cell death in objective of this study was to investigate the underlying molecular psoriatic lesions, single-cell RNA sequencing data (scRNA-seq) mechanism of ferroptosis and its role in the pathogenic process of from eight samples were analyzed. Visualization of the 15 main clusters was depicted in a single UMAP plot (Fig. 2A), and markers

RESULTS

METHODS

Findings

ETHICS STATEMENT