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Pilot study of the role of ferroptosis in abnormal biological behaviour of keratinocytes in psoriasis vulgaris

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Abstract

Background

Abnormal biological behaviour of keratinocytes (KCs) is a critical pathophysiological manifestation of psoriasis. Ferroptosis is programmed cell death induced by the accumulation of lipid reactive oxygen species (ROS) in the presence of increased intracellular iron ions or inhibition of GPX4.

Objectives

The purpose of this study was to investigate the effects of ferroptosis on the biological behaviour of Keratinocytes (KCs) in psoriasis vulgaris and its possible regulatory mechanisms in clinical samples, cells, and mouse models.

Methods

We first examined the differences in the expression of GPX4 and 4-HNE between psoriasis and normal human lesions. And detected KRT6, FLG, and inflammatory cytokines after inducing ferroptosis in animal and cell models by RT-qPCR, Western blot, immunohistochemistry, and flow cytometry.

Results

We found that GPX4 was decreased and that the oxidation product 4-hydroxy-2-nonenal (HNE) was increased in the skin lesions of patients with psoriasis vulgaris. The expression level of GPX4 correlates with the severity of skin lesions. Moreover, inducing ferroptosis promoted the expression of FLG and reduced the expression of KRT6 and inflammatory cytokines in vitro, and alleviated the phenotype of skin lesions in vivo.

Limitations

Our study has limitations, notably small sample size. Larger clinical trials are necessary to investigate the association between ferroptosis and disease progression further. More research is necessary to explore how the ferroptosis inducer RSL3 regulates the abnormal biological behaviour of KCs at both cellular and animal levels and establish ferroptosis inhibitors as controls.

Conclusions

This study confirms the existence of ferroptosis in psoriatic lesions, which may be inversely correlated with disease severity. The ferroptosis inducer RSL3 ameliorated psoriatic symptoms by improving the abnormal biological behaviour of KCs.

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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

KCs:

keratinocytes

GPX4:

glutathione peroxidase 4

IMQ:

imiquimod

Th:

T helper cells

TNF:

tumour necrosis factor

IL:

interleukin

CXCL:

C-X-C motif chemokine ligand

CCL:

C-C motif chemokine ligand

GSH:

glutathione

Xc― :

cystine/glutamate transporter

ROS:

reactive oxygen species

4HNE:

4-Hydroxynonenal

KRT:

keratin

FLG:

filaggrin

PI:

propidium iodide

HE:

hematoxylin and eosin stain

PASI:

psoriasis area and severity index

Ctrl:

control

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Author notes

  1. Ningling Wu and Qian Hu authors are considered co-first authors.

Authors and Affiliations

  1. Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China

    Ningling Wu, Zhibing Fu, Xiaoliang Tong, Lihua Gao, Lina Tan, Siyu Yan, Dan Wang, Jinrong Zeng, Jianyun Lu & Wenchuan Li

  2. Department of Dermatology, Changsha Fourth Hospital, Changsha, 410006, Hunan, China

    Qian Hu

  3. The Third Xiangya Hospital, Central South University, No.138 Tongzipo Rd, Yuelu District, Changsha, 410013, Hunan, China

    Wenchuan Li

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Contributions

Wenchuan Li: Conceptualization and Supervision. Jinrong Zeng, Lu zhou, and Zhibing Fu: Writing- Original draft preparation. Qian Hu, Ningling Wu: Investigation, Methodology and Formal analysis. Ningling Wu: Visualization. Xiaoliang Tong: Validation. Lina Tan, Siyu Yan, Lihua Gao, and Dan Wang: Data Curation. Wenchuan Li: Writing - Review & Editing. All authors read and approved the final manuscript.

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Correspondence to Wenchuan Li.

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Wu, N., Hu, Q., Fu, Z. et al. Article file. Arch Dermatol Res 316, 604 (2024). https://doi.org/10.1007/s00403-024-03345-x

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