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Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation

Psoriasis is a common autoimmune and chronic inflammatory skin disorder globally affecting 0.51–11.43% of adults. Inflammation-associated cell death in keratinocytes plays a key role in the process of integrate inflammatory cascade in psoriasis. Necroptosis is a regulated necrotic cell death mediate...

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Autores principales: Duan, Xiaoru, Liu, Xinxin, Liu, Nian, Huang, Yuqiong, Jin, Zilin, Zhang, Song, Ming, Zhangyin, Chen, Hongxiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031250/
https://www.ncbi.nlm.nih.gov/pubmed/32075957
http://dx.doi.org/10.1038/s41419-020-2328-0
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author Duan, Xiaoru
Liu, Xinxin
Liu, Nian
Huang, Yuqiong
Jin, Zilin
Zhang, Song
Ming, Zhangyin
Chen, Hongxiang
author_facet Duan, Xiaoru
Liu, Xinxin
Liu, Nian
Huang, Yuqiong
Jin, Zilin
Zhang, Song
Ming, Zhangyin
Chen, Hongxiang
author_sort Duan, Xiaoru
collection PubMed
description Psoriasis is a common autoimmune and chronic inflammatory skin disorder globally affecting 0.51–11.43% of adults. Inflammation-associated cell death in keratinocytes plays a key role in the process of integrate inflammatory cascade in psoriasis. Necroptosis is a regulated necrotic cell death mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), which participates in many human inflammatory diseases. However, the mechanism and function of programmed necrosis in psoriasis is not well-illustrated. In the current study, we provide evidence for the involvement of necroptosis in psoriasis. RIPK1 and MLKL were significantly upregulated and localized in all layers of the epidermis in human psoriatic lesions, while RIPK3 and phosphorylated MLKL were mainly expressed in keratinocytes, which located in the upper layers. Increased tendency of necroptosis was also found in IMQ-induced psoriasiform skin of mice. Further, we discovered that both the inhibitor of RIPK1 R-7-Cl-O-Necrostatin-1 (Nec-1s) and MLKL-inhibitor necrosulfonamide (NSA) suppressed necroptosis in HaCaT cells and IMQ mouse models, powerfully blocked IMQ-induced inflammatory responses in vivo, and significantly downregulated the production of inflammatory factors like IL-1β, IL-6, IL-17A, IL-23a, CXCL1, and CCL20. These findings promote the development of new therapies for the treatment of necroptosis-activated pathologies for psoriasis.
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spelling pubmed-70312502020-02-25 Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation Duan, Xiaoru Liu, Xinxin Liu, Nian Huang, Yuqiong Jin, Zilin Zhang, Song Ming, Zhangyin Chen, Hongxiang Cell Death Dis Article Psoriasis is a common autoimmune and chronic inflammatory skin disorder globally affecting 0.51–11.43% of adults. Inflammation-associated cell death in keratinocytes plays a key role in the process of integrate inflammatory cascade in psoriasis. Necroptosis is a regulated necrotic cell death mediated by receptor interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL), which participates in many human inflammatory diseases. However, the mechanism and function of programmed necrosis in psoriasis is not well-illustrated. In the current study, we provide evidence for the involvement of necroptosis in psoriasis. RIPK1 and MLKL were significantly upregulated and localized in all layers of the epidermis in human psoriatic lesions, while RIPK3 and phosphorylated MLKL were mainly expressed in keratinocytes, which located in the upper layers. Increased tendency of necroptosis was also found in IMQ-induced psoriasiform skin of mice. Further, we discovered that both the inhibitor of RIPK1 R-7-Cl-O-Necrostatin-1 (Nec-1s) and MLKL-inhibitor necrosulfonamide (NSA) suppressed necroptosis in HaCaT cells and IMQ mouse models, powerfully blocked IMQ-induced inflammatory responses in vivo, and significantly downregulated the production of inflammatory factors like IL-1β, IL-6, IL-17A, IL-23a, CXCL1, and CCL20. These findings promote the development of new therapies for the treatment of necroptosis-activated pathologies for psoriasis. Nature Publishing Group UK 2020-02-19 /pmc/articles/PMC7031250/ /pubmed/32075957 http://dx.doi.org/10.1038/s41419-020-2328-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Duan, Xiaoru
Liu, Xinxin
Liu, Nian
Huang, Yuqiong
Jin, Zilin
Zhang, Song
Ming, Zhangyin
Chen, Hongxiang
Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
title Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
title_full Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
title_fullStr Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
title_full_unstemmed Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
title_short Inhibition of keratinocyte necroptosis mediated by RIPK1/RIPK3/MLKL provides a protective effect against psoriatic inflammation
title_sort inhibition of keratinocyte necroptosis mediated by ripk1/ripk3/mlkl provides a protective effect against psoriatic inflammation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031250/
https://www.ncbi.nlm.nih.gov/pubmed/32075957
http://dx.doi.org/10.1038/s41419-020-2328-0
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