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A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis
Atopic dermatitis (AD) is a common chronic pruritic inflammatory skin disorder characterized by recurrent eczematous lesions. Interleukin (IL)−33, a cytokine of the IL-1 family, was found to play an important role in the pathogenesis of AD. As a key component of the inflammasome, NLRP3 has been most...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463682/ https://www.ncbi.nlm.nih.gov/pubmed/34561424 http://dx.doi.org/10.1038/s41419-021-04159-9 |
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author | Zheng, Jie Yao, Lu Zhou, Yijing Gu, Xiaoqun Wang, Can Bao, Kaifan Sun, Yang Hong, Min |
author_facet | Zheng, Jie Yao, Lu Zhou, Yijing Gu, Xiaoqun Wang, Can Bao, Kaifan Sun, Yang Hong, Min |
author_sort | Zheng, Jie |
collection | PubMed |
description | Atopic dermatitis (AD) is a common chronic pruritic inflammatory skin disorder characterized by recurrent eczematous lesions. Interleukin (IL)−33, a cytokine of the IL-1 family, was found to play an important role in the pathogenesis of AD. As a key component of the inflammasome, NLRP3 has been mostly described in myeloid cells that to mediate inflammasome activation conducted proinflammatory cytokine production of the IL-1 family. However, the role of NLRP3 inflammasome in the pathogenesis of AD, as well as IL-33 processing are highly controversial. Whether NLRP3 can mediate IL-33 expression and secretion independently of the inflammasome in the epithelium of AD has remained unclear. In this article, we found the mRNA expression of Il33 and Nlrp3 were notably increased in the lesional skin of AD patients compared to healthy controls. We then found a significant positive correlation between the expression of Nlrp3 and Il33 in the epithelium of MC903-mediated AD mice model, but no changes were observed for Il36α, Il36γ, Il1β, or Il18 mRNA expression, as well as IL-1β or IL-18 production. Overexpression of NLRP3 in human immortalized epithelial cells increased IL-33 expression, whereas siRNA targeting NLRP3 abolished IL-33 expression. In addition, inhibition of NLRP3 inflammasome activation or caspase-1 activity with MCC950 or VX-765 showed no effect on the expression and secretion of IL-33 in AD mice. Unlike myeloid cells, NLRP3 predominantly located in the nucleus of epithelial cells, which could directly bind to Il33 specific-promoters and transactivate it through an interaction with transcription factor IRF4. Furthermore, NLRP3 deficient mice exhibited a significant alleviated epidermis inflammation and decreased mRNA expression and secretion of IL-33 in MC903-mediated AD mice without interfering with TSLP and IL-1β production. Our results demonstrate a novel ability of NLRP3 to function as a crucial transcription factor of IL-33 in epithelium independently of inflammasome that to mediate the pathological process of AD. |
format | Online Article Text |
id | pubmed-8463682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84636822021-10-08 A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis Zheng, Jie Yao, Lu Zhou, Yijing Gu, Xiaoqun Wang, Can Bao, Kaifan Sun, Yang Hong, Min Cell Death Dis Article Atopic dermatitis (AD) is a common chronic pruritic inflammatory skin disorder characterized by recurrent eczematous lesions. Interleukin (IL)−33, a cytokine of the IL-1 family, was found to play an important role in the pathogenesis of AD. As a key component of the inflammasome, NLRP3 has been mostly described in myeloid cells that to mediate inflammasome activation conducted proinflammatory cytokine production of the IL-1 family. However, the role of NLRP3 inflammasome in the pathogenesis of AD, as well as IL-33 processing are highly controversial. Whether NLRP3 can mediate IL-33 expression and secretion independently of the inflammasome in the epithelium of AD has remained unclear. In this article, we found the mRNA expression of Il33 and Nlrp3 were notably increased in the lesional skin of AD patients compared to healthy controls. We then found a significant positive correlation between the expression of Nlrp3 and Il33 in the epithelium of MC903-mediated AD mice model, but no changes were observed for Il36α, Il36γ, Il1β, or Il18 mRNA expression, as well as IL-1β or IL-18 production. Overexpression of NLRP3 in human immortalized epithelial cells increased IL-33 expression, whereas siRNA targeting NLRP3 abolished IL-33 expression. In addition, inhibition of NLRP3 inflammasome activation or caspase-1 activity with MCC950 or VX-765 showed no effect on the expression and secretion of IL-33 in AD mice. Unlike myeloid cells, NLRP3 predominantly located in the nucleus of epithelial cells, which could directly bind to Il33 specific-promoters and transactivate it through an interaction with transcription factor IRF4. Furthermore, NLRP3 deficient mice exhibited a significant alleviated epidermis inflammation and decreased mRNA expression and secretion of IL-33 in MC903-mediated AD mice without interfering with TSLP and IL-1β production. Our results demonstrate a novel ability of NLRP3 to function as a crucial transcription factor of IL-33 in epithelium independently of inflammasome that to mediate the pathological process of AD. Nature Publishing Group UK 2021-09-24 /pmc/articles/PMC8463682/ /pubmed/34561424 http://dx.doi.org/10.1038/s41419-021-04159-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zheng, Jie Yao, Lu Zhou, Yijing Gu, Xiaoqun Wang, Can Bao, Kaifan Sun, Yang Hong, Min A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis |
title | A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis |
title_full | A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis |
title_fullStr | A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis |
title_full_unstemmed | A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis |
title_short | A novel function of NLRP3 independent of inflammasome as a key transcription factor of IL-33 in epithelial cells of atopic dermatitis |
title_sort | novel function of nlrp3 independent of inflammasome as a key transcription factor of il-33 in epithelial cells of atopic dermatitis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463682/ https://www.ncbi.nlm.nih.gov/pubmed/34561424 http://dx.doi.org/10.1038/s41419-021-04159-9 |
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