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Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs
In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the di...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606375/ https://www.ncbi.nlm.nih.gov/pubmed/36289219 http://dx.doi.org/10.1038/s41467-022-33767-y |
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author | Wang, Wenxia Bale, Swarna Wei, Jun Yalavarthi, Bharath Bhattacharyya, Dibyendu Yan, Jing Jing Abdala-Valencia, Hiam Xu, Dan Sun, Hanshi Marangoni, Roberta G. Herzog, Erica Berdnikovs, Sergejs Miller, Stephen D. Sawalha, Amr H. Tsou, Pei-Suen Awaji, Kentaro Yamashita, Takashi Sato, Shinichi Asano, Yoshihide Tiruppathi, Chinnaswamy Yeldandi, Anjana Schock, Bettina C. Bhattacharyya, Swati Varga, John |
author_facet | Wang, Wenxia Bale, Swarna Wei, Jun Yalavarthi, Bharath Bhattacharyya, Dibyendu Yan, Jing Jing Abdala-Valencia, Hiam Xu, Dan Sun, Hanshi Marangoni, Roberta G. Herzog, Erica Berdnikovs, Sergejs Miller, Stephen D. Sawalha, Amr H. Tsou, Pei-Suen Awaji, Kentaro Yamashita, Takashi Sato, Shinichi Asano, Yoshihide Tiruppathi, Chinnaswamy Yeldandi, Anjana Schock, Bettina C. Bhattacharyya, Swati Varga, John |
author_sort | Wang, Wenxia |
collection | PubMed |
description | In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy. |
format | Online Article Text |
id | pubmed-9606375 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-96063752022-10-28 Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs Wang, Wenxia Bale, Swarna Wei, Jun Yalavarthi, Bharath Bhattacharyya, Dibyendu Yan, Jing Jing Abdala-Valencia, Hiam Xu, Dan Sun, Hanshi Marangoni, Roberta G. Herzog, Erica Berdnikovs, Sergejs Miller, Stephen D. Sawalha, Amr H. Tsou, Pei-Suen Awaji, Kentaro Yamashita, Takashi Sato, Shinichi Asano, Yoshihide Tiruppathi, Chinnaswamy Yeldandi, Anjana Schock, Bettina C. Bhattacharyya, Swati Varga, John Nat Commun Article In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy. Nature Publishing Group UK 2022-10-26 /pmc/articles/PMC9606375/ /pubmed/36289219 http://dx.doi.org/10.1038/s41467-022-33767-y Text en © The Author(s) 2022, corrected publication 2023 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 Wang, Wenxia Bale, Swarna Wei, Jun Yalavarthi, Bharath Bhattacharyya, Dibyendu Yan, Jing Jing Abdala-Valencia, Hiam Xu, Dan Sun, Hanshi Marangoni, Roberta G. Herzog, Erica Berdnikovs, Sergejs Miller, Stephen D. Sawalha, Amr H. Tsou, Pei-Suen Awaji, Kentaro Yamashita, Takashi Sato, Shinichi Asano, Yoshihide Tiruppathi, Chinnaswamy Yeldandi, Anjana Schock, Bettina C. Bhattacharyya, Swati Varga, John Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs |
title | Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs |
title_full | Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs |
title_fullStr | Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs |
title_full_unstemmed | Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs |
title_short | Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs |
title_sort | fibroblast a20 governs fibrosis susceptibility and its repression by dream promotes fibrosis in multiple organs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606375/ https://www.ncbi.nlm.nih.gov/pubmed/36289219 http://dx.doi.org/10.1038/s41467-022-33767-y |
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