Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation
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 recognize...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04284-5 |
| _version_ | 1819116876913967104 |
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| author | Yanhong Shou Lu Yang Yongsheng Yang Jinhua Xu |
| author_facet | Yanhong Shou Lu Yang Yongsheng Yang Jinhua Xu |
| author_sort | Yanhong Shou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T05:24:04Z |
| format | Article |
| id | doaj.art-e7c651e98fd749ccb6f459abdfe995bb |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-22T05:24:04Z |
| publishDate | 2021-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-e7c651e98fd749ccb6f459abdfe995bb2022-12-21T18:37:39ZengNature Publishing GroupCell Death and Disease2041-48892021-10-01121111010.1038/s41419-021-04284-5Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammationYanhong Shou0Lu Yang1Yongsheng Yang2Jinhua Xu3Department of Dermatology, Huashan Hospital, Fudan UniversityDepartment of Dermatology, Huashan Hospital, Fudan UniversityDepartment of Dermatology, Huashan Hospital, Fudan UniversityDepartment of Dermatology, Huashan Hospital, Fudan UniversityAbstract 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.https://doi.org/10.1038/s41419-021-04284-5 |
| spellingShingle | Yanhong Shou Lu Yang Yongsheng Yang Jinhua Xu Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation Cell Death and Disease |
| title | Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation |
| title_full | Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation |
| title_fullStr | Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation |
| title_full_unstemmed | Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation |
| title_short | Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation |
| title_sort | inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation |
| url | https://doi.org/10.1038/s41419-021-04284-5 |
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