Ferrostatin-1 alleviates skin inflammation and inhibits ferroptosis of neutrophils and CD8+ T cells in allergic contact dermatitis

Abstract

Background: Ferroptosis is considered as an immunogenic type of regulated cell death and associated with the pathogenesis of inflammatory skin diseases. However, the involvement and function of ferroptosis in allergic contact dermatitis (ACD) remains unknown.

Objective: To explore the role of ferroptosis in ACD. To reveal which type of cells develops ferroptosis in ACD.

Methods: We detected the key markers of ferroptosis in 1-Chloro-2,4-dinitrochlorobenzene (DNCB)-induced ACD mice model. We applicated ferrostatin-1 (Fer-1) to restrain ferroptosis in ACD mice and then compared the severity of dermatitis and the level of inflammation and ferroptosis in dermis and epidermis, respectively. Keratinocyte-specific Gpx4 conditional knockout (cKO) mice were used to investigate the function of keratinocyte ferroptosis in the development of ACD. Single-cell RNA sequencing was conducted to analyze the affection of Fer-1 on different type of cells in ACD.

Results: Ferroptosis was involved in DNCB-induced ACD mice. Ferroptosis activation was more remarkable in dermis rather than in epidermis. Gpx4 cKO mice showed similar severity of skin dermatitis as control mice. Fer-1 alleviated skin inflammation in mice and reduced ferroptosis in neutrophils and CD8⁺ T cells both of which contribute to development of ACD.

Conclusion: Ferroptosis was activated in immune cells, especially neutrophils and CD8⁺ T cells in DNCB-induced ACD mice. Fer-1 treatment inhibited ferroptosis of neutrophils and CD8⁺ T cells and relieved skin damage in ACD mice.

Keywords: Allergic contact dermatitis; CD8(+) T cell; Ferroptosis; Ferrostatin-1; Neutrophil.